Pathophysiology and Therapeutic Strategies for Opioid Addiction

**41**

**Chapter 4**

**Abstract**

Opiate Addiction

*and María Luisa Laorden*

Role of Glucocorticoid Receptor

*Javier Navarro-Zaragoza, María Victoria Milanés* 

noradrenergic release in the paraventricular nucleus (PVN).

noradrenergic system, TH, ERK, CREB

**1. Introduction**

withdrawal [2].

**Keywords:** glucocorticoids, stress, addiction, brain stress system,

Drug addiction is a chronic disease characterized by recurrence of its signs:

Drug addiction has been described as a three-phase disease: During phase 1, drug- seeking behavior is exacerbated and it courses with sensibilization of dopaminergic system, altogether with an associative learning from environment [3]. Phase 2 consists of positive reinforcement pathway downregulation [4]. Finally, phase 3

drug-seeking and drug-taking behavior, loss of control and impulsivity in consumption, and emergence of a negative state when the access to the drug is not possible [1]. Besides, drug relapse is very often even months and years after

in the Relation between Stress and

Stressful situations can result in relapse in dependent or abstinent causing reinstatement of drug-seeking. In fact, it has been suggested that activation of the brain stress system results in glucocorticoid release that affects the dopaminergic pathways. Also, the noradrenergic system innervates the extrahypothalamic BSS from the nucleus of tractus solitarius (NTS), resulting in a feedforward loop between the corticotropin-releasing factor (CRF) and noradrenaline (NA) crucial in drug addiction and relapses. Glucocorticoids interact with two receptors: mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) which bind to a GRE site located in tyrosine hydroxylase (TH), resulting in the upregulation of TH synthesis and, finally, increasing dopamine (DA) release in the nucleus accumbens. TH upregulation depends on the phosphorylation of serine 31 and/or serine 40. Previous research has shown that protein kinase C (PKC) activates extracellular signal-regulated kinase (ERK) pathway and in turn phosphorylates serine 31 in the NTS. Besides, cAMP response element binding protein (CREB) is regulated by PKA and PKC. The results shown after pretreating morphine-withdrawn rats with mifepristone and spironolactone (GR and MR antagonists, respectively) suggest that glucocorticoids have a prominent role in addiction because GR would activate ERK and CREB in the NTS, phosphorylating serine 31 and activating TH and indeed

### **Chapter 4**

## Role of Glucocorticoid Receptor in the Relation between Stress and Opiate Addiction

*Javier Navarro-Zaragoza, María Victoria Milanés and María Luisa Laorden*

### **Abstract**

Stressful situations can result in relapse in dependent or abstinent causing reinstatement of drug-seeking. In fact, it has been suggested that activation of the brain stress system results in glucocorticoid release that affects the dopaminergic pathways. Also, the noradrenergic system innervates the extrahypothalamic BSS from the nucleus of tractus solitarius (NTS), resulting in a feedforward loop between the corticotropin-releasing factor (CRF) and noradrenaline (NA) crucial in drug addiction and relapses. Glucocorticoids interact with two receptors: mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) which bind to a GRE site located in tyrosine hydroxylase (TH), resulting in the upregulation of TH synthesis and, finally, increasing dopamine (DA) release in the nucleus accumbens. TH upregulation depends on the phosphorylation of serine 31 and/or serine 40. Previous research has shown that protein kinase C (PKC) activates extracellular signal-regulated kinase (ERK) pathway and in turn phosphorylates serine 31 in the NTS. Besides, cAMP response element binding protein (CREB) is regulated by PKA and PKC. The results shown after pretreating morphine-withdrawn rats with mifepristone and spironolactone (GR and MR antagonists, respectively) suggest that glucocorticoids have a prominent role in addiction because GR would activate ERK and CREB in the NTS, phosphorylating serine 31 and activating TH and indeed noradrenergic release in the paraventricular nucleus (PVN).

**Keywords:** glucocorticoids, stress, addiction, brain stress system, noradrenergic system, TH, ERK, CREB

### **1. Introduction**

Drug addiction is a chronic disease characterized by recurrence of its signs: drug-seeking and drug-taking behavior, loss of control and impulsivity in consumption, and emergence of a negative state when the access to the drug is not possible [1]. Besides, drug relapse is very often even months and years after withdrawal [2].

Drug addiction has been described as a three-phase disease: During phase 1, drug- seeking behavior is exacerbated and it courses with sensibilization of dopaminergic system, altogether with an associative learning from environment [3]. Phase 2 consists of positive reinforcement pathway downregulation [4]. Finally, phase 3

is characterized by a negative emotional state and by an enhanced craving, which facilitates relapse to drug addiction [5]. Summarizing, individuals experience positive reinforcement in early stages of addiction when they consume drugs of abuse, but after several intakes, they continue that consumption only to avoid the negative state that appears during withdrawal [2, 6].

Previous research has described the importance of different neurotransmitters and neuronal systems in the distinct phases of addiction, being dopaminergic system the main responsible of positive reinforcement [7–10]. Differently, noradrenergic system and brain stress system activities are increased during drug dependence [11].

It is well known that dopaminergic system innervates the prefrontal cortex (PFC) and the nucleus accumbens (NAc), where consumption of major drugs of abuse produces dopamine (DA) release, what is attributed to be behind the development of drug addiction due to its positive reinforcement properties. In contrast, noradrenergic system is mainly related with the negative state that emerges when there is drug withdrawal. It has been shown that noradrenergic innervation from nucleus of tractus solitarius (NTS) to the paraventricular nucleus (PVN) is involved in drug-seeking and in the negative reinforcement produced by morphine withdrawal [12, 13]. Moreover, the existence of a loop between noradrenaline (NA) and corticotropin-releasing factor (CRF) has been described where the enhancement of NA system would result in the enhancement of CRF release (feedforward) and vice versa [14].

On the other hand, many pathways are involved in drug addiction resulting in intracellular responses once extracellular stimuli are processed. One of the more critical is the extracellular signal-regulated kinases (ERK) pathway which plays a main role in neuronal changes, being implicated, i.e., in reward after cocaine consumption [15]. Also, cAMP response element binding protein (CREB) is crucial being its activation through phosphorylation (pCREB). Previous studies from our laboratory have suggested an enhancement of pCREB during morphine withdrawal in the NTS [16]. Besides, CREB regulates TH phosphorylation, limiting enzyme for DA synthesis.

### **2. Brain stress system and addiction**

Brain stress system is composed of two different linked structures: hypothalamic-pituitary-adrenal (HPA) axis and the extended amygdala [17]. Both structures are activated during drug intake and during withdrawal, resulting in CRF and glucocorticoid release [18].

### **2.1 HPA axis**

Also known as hypothalamic brain stress system, as its name suggests, it is divided in three components: the PVN, the pituitary, and the suprarenal glands [1, 12, 19]. In the PVN, CRF is released from the medial parvocellular subdivision to the median eminence reaching the pituitary (**Figure 1**) where it stimulates the synthesis and release of adrenocorticotropic hormone (ACTH) through CRF1R and CRF2R activation [20, 21]. Consequently, ACTH stimulates the synthesis and release of glucocorticoids from the adrenal glands. These glucocorticoids regulate the HPA axis through a negative feedback system once they interact with glucocorticoid (GR) and mineralocorticoid receptors (MR). Changes in this system are proposed to mediate transition from acute consumption to chronic consumption in

**43**

models [26].

**Figure 1.**

**2.2 Extended amygdala**

*Role of Glucocorticoid Receptor in the Relation between Stress and Opiate Addiction*

addicted [12, 22]. Previous research has shown that different antagonists can block the negative state that come across during morphine withdrawal [23]. Besides, chronic exposure to opiates results in physic dependence and tolerance, and it is accompanied by enhanced ACTH and corticosterone release during morphine withdrawal [24]. Stressful situations can result in relapse in dependent or abstinent humans [25] and cause reinstatement of drug-seeking in different animal relapsing

*Representation of the HPA axis. The hypothalamic brain stress system or HPA axis is composed by the PVN, the pituitary, and the suprarenal glands. CRF binds to CRF1R and CRF2R resulting in the activation of the pituitary which consequently, through ACTH, produces release of glucocorticoids (corticosterone, CORT) by the* 

*adrenal glands resulting in negative feedback over the previous steps.*

The extrahypothalamic brain stress system or the extended amygdala (**Figure 2**)

is composed of different nuclei as bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CeA), and the shell of the NAc [27, 28]. These nuclei have similar functions and are responsible of connecting the limbic structures as hippocampus, basolateral amygdala, or the midbrain [12, 29]. Also, limbic structures mediate responses and behavior guiding the individuals according to memories [30]. Here, CRF receptors and CRF neuron cell bodies have been seen in BNST and CeA innervating each other and others as the NAc [28, 31, 32]. Therefore, CRF has a prominent role in this structure. Moreover, the extended amygdala is a key component in the acquisition and development of different negative symptoms through the release of CRF together with other neurotransmitters or peptides like NA or dynorphin [17, 33, 34]. In addition, extended amygdala is linked to the NTS (a noradrenergic nucleus) through innervations from there to the BNST, CeA, or the NAc [35, 36]. Thereupon, the extended amygdala, a part of the brain stress system, connects with the noradrenergic system and the dopaminergic pathways [37]. In fact, it has been suggested that activation of the brain stress system would

result in sensibilization of the dopaminergic pathways [38, 39].

*DOI: http://dx.doi.org/10.5772/intechopen.90839*

*Role of Glucocorticoid Receptor in the Relation between Stress and Opiate Addiction DOI: http://dx.doi.org/10.5772/intechopen.90839*

### **Figure 1.**

*Opioids - From Analgesic Use to Addiction*

dependence [11].

versa [14].

DA synthesis.

**2.1 HPA axis**

**2. Brain stress system and addiction**

glucocorticoid release [18].

state that appears during withdrawal [2, 6].

is characterized by a negative emotional state and by an enhanced craving, which facilitates relapse to drug addiction [5]. Summarizing, individuals experience positive reinforcement in early stages of addiction when they consume drugs of abuse, but after several intakes, they continue that consumption only to avoid the negative

Previous research has described the importance of different neurotransmitters and neuronal systems in the distinct phases of addiction, being dopaminergic system the main responsible of positive reinforcement [7–10]. Differently, noradrenergic system and brain stress system activities are increased during drug

It is well known that dopaminergic system innervates the prefrontal cortex (PFC) and the nucleus accumbens (NAc), where consumption of major drugs of abuse produces dopamine (DA) release, what is attributed to be behind the development of drug addiction due to its positive reinforcement properties. In contrast, noradrenergic system is mainly related with the negative state that emerges when there is drug withdrawal. It has been shown that noradrenergic innervation from nucleus of tractus solitarius (NTS) to the paraventricular nucleus (PVN) is involved in drug-seeking and in the negative reinforcement produced by morphine withdrawal [12, 13]. Moreover, the existence of a loop between noradrenaline (NA) and corticotropin-releasing factor (CRF) has been described where the enhancement of NA system would result in the enhancement of CRF release (feedforward) and vice

On the other hand, many pathways are involved in drug addiction resulting in intracellular responses once extracellular stimuli are processed. One of the more critical is the extracellular signal-regulated kinases (ERK) pathway which plays a main role in neuronal changes, being implicated, i.e., in reward after cocaine consumption [15]. Also, cAMP response element binding protein (CREB) is crucial being its activation through phosphorylation (pCREB). Previous studies from our laboratory have suggested an enhancement of pCREB during morphine withdrawal in the NTS [16]. Besides, CREB regulates TH phosphorylation, limiting enzyme for

Brain stress system is composed of two different linked structures: hypothalamic-pituitary-adrenal (HPA) axis and the extended amygdala [17]. Both structures are activated during drug intake and during withdrawal, resulting in CRF and

Also known as hypothalamic brain stress system, as its name suggests, it is divided in three components: the PVN, the pituitary, and the suprarenal glands [1, 12, 19]. In the PVN, CRF is released from the medial parvocellular subdivision to the median eminence reaching the pituitary (**Figure 1**) where it stimulates the synthesis and release of adrenocorticotropic hormone (ACTH) through CRF1R and CRF2R activation [20, 21]. Consequently, ACTH stimulates the synthesis and release of glucocorticoids from the adrenal glands. These glucocorticoids regulate the HPA axis through a negative feedback system once they interact with glucocorticoid (GR) and mineralocorticoid receptors (MR). Changes in this system are proposed to mediate transition from acute consumption to chronic consumption in

**42**

*Representation of the HPA axis. The hypothalamic brain stress system or HPA axis is composed by the PVN, the pituitary, and the suprarenal glands. CRF binds to CRF1R and CRF2R resulting in the activation of the pituitary which consequently, through ACTH, produces release of glucocorticoids (corticosterone, CORT) by the adrenal glands resulting in negative feedback over the previous steps.*

addicted [12, 22]. Previous research has shown that different antagonists can block the negative state that come across during morphine withdrawal [23]. Besides, chronic exposure to opiates results in physic dependence and tolerance, and it is accompanied by enhanced ACTH and corticosterone release during morphine withdrawal [24]. Stressful situations can result in relapse in dependent or abstinent humans [25] and cause reinstatement of drug-seeking in different animal relapsing models [26].

### **2.2 Extended amygdala**

The extrahypothalamic brain stress system or the extended amygdala (**Figure 2**) is composed of different nuclei as bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CeA), and the shell of the NAc [27, 28]. These nuclei have similar functions and are responsible of connecting the limbic structures as hippocampus, basolateral amygdala, or the midbrain [12, 29]. Also, limbic structures mediate responses and behavior guiding the individuals according to memories [30]. Here, CRF receptors and CRF neuron cell bodies have been seen in BNST and CeA innervating each other and others as the NAc [28, 31, 32]. Therefore, CRF has a prominent role in this structure. Moreover, the extended amygdala is a key component in the acquisition and development of different negative symptoms through the release of CRF together with other neurotransmitters or peptides like NA or dynorphin [17, 33, 34]. In addition, extended amygdala is linked to the NTS (a noradrenergic nucleus) through innervations from there to the BNST, CeA, or the NAc [35, 36]. Thereupon, the extended amygdala, a part of the brain stress system, connects with the noradrenergic system and the dopaminergic pathways [37]. In fact, it has been suggested that activation of the brain stress system would result in sensibilization of the dopaminergic pathways [38, 39].

### **Figure 2.**

*Representation of the extended amygdala. The extrahypothalamic brain stress system or extended amygdala is shown here in a scheme with its main nuclei: BNST, CeA, and NAc. Noradrenergic innervations establish a feedforward loop between CRF and NA, which remains crucial for the development of drug addiction and relapses. Besides, there is dopaminergic innervation from ventral tegmental area to different nuclei establishing a relationship between NA system, DA system, and the brain stress system (hypothalamic and extrahypothalamic).*

### **3. Role of glucocorticoids in addiction**

Glucocorticoids are the final step of HPA axis, and their release takes place in response to stressful situations, becoming this activation one of the main mechanisms of adaption to stress [40]. Glucocorticoids make their function by interacting with two classes of receptors: MR or type I and GR or type II [41].

Whereas MR are located in limbic areas of the brain such as amygdala and also in the PVN or the locus coeruleus (LC) [42], GR have a more heterogeneous localization, with deep presence in the PVN, amygdala, or the hippocampus. MR have higher affinity for corticosterone than GR, but GR are activated when there are stressful facts differently to MR, which are important at basal levels. Both receptors have presence in the NTS, making this nucleus to be important in glucocorticoid effects [43]. Previous research has shown that MR blockade decreases self-administration of cocaine, suggesting a role for these receptors in addiction [44].

Moreover, stress affects GR, which are located through the dopaminergic pathways enhancing HPA axis and dopaminergic activity. In fact, glucocorticoids have been suggested to interact with a GRE site located in TH, resulting in the upregulation of TH synthesis and, finally, increasing DA release in the NAc [45]. Therefore, individuals with higher HPA axis activity would be more vulnerable to develop drug addiction [5].

### **4. Involvement of GR and MR in TH activity and phosphorylation in the NTS**

The regulation in the biosynthesis of catecholamines by TH depends on its phosphorylation at serine 31 and serine 40. This has been proposed to be triggered by stressful situations considering that increased release of glucocorticoids results in uprising TH activity [46]. Moreover, morphine withdrawal induced by naloxone injection increased TH mRNA expression in the NTS and TH activity in the PVN [47]. Therefore, it was critical to elucidate if blocking GR and MR with mifepristone and

**45**

*\**

**Figure 3.**

*placebo + spironolactone + naloxone.*

*Role of Glucocorticoid Receptor in the Relation between Stress and Opiate Addiction*

spironolactone would affect TH phosphorylation during morphine withdrawal in the NTS. Results from our laboratory showed that TH phosphorylation at serine 31 and serine 40 was increased during naloxone-induced morphine withdrawal in rats, a fact that, together with the existence of enhanced NA turnover in the NTS during morphine withdrawal, suggests that TH regulates noradrenergic activity [24, 31, 48–50]. Besides, the blockade of GR with mifepristone, selective antagonist of GR, significantly attenuated the phosphorylation at serine 31, but not at serine 40 in the NTS during morphine withdrawal [48, 50], different to the results after blockade of MR with spironolactone. Pretreatment with this antagonist decreased phosphorylation of serine 31 in the NTS but not significantly [49, 50] (**Figure 3**). These results would suggest that enhanced glucocorticoid release during morphine withdrawal results in TH phosphorylation at serine 31, consequently, also in enhanced TH activity, and finally in higher catecholamine levels in the PVN, innervated by noradrenergic system.

*Antagonization of TH phosphorylation at serine 31 by mifepristone (GR antagonist). Mifepristone (C) but not spironolactone (A) antagonized naloxone-induced morphine-withdrawal phosphorylation of TH at serine 31 in the NTS. Representative immunoblots of THpSer31 (A, C) and THpSer40 (B, D) in the NTS tissues isolated from placebo and morphine-dependent rats 60 min after administration of naloxone and the respective antagonist [mifepristone (C, D) or spironolactone (A, B)] or saline. Data represent the optical density of immunoreactive bands expressed as a percentage (%) of the mean ± SEM of placebo control band* 

*morphine + vehicle + naloxone; ++P < 0.01 versus placebo + spironolactone+ naloxone; +++P < 0.001 versus* 

*P < 0.05 versus* 

*P < 0.05 versus placebo + vehicle + naloxone; \*\*P < 0.01 versus placebo + vehicle + naloxone; #*

*DOI: http://dx.doi.org/10.5772/intechopen.90839*

### *Role of Glucocorticoid Receptor in the Relation between Stress and Opiate Addiction DOI: http://dx.doi.org/10.5772/intechopen.90839*

spironolactone would affect TH phosphorylation during morphine withdrawal in the NTS. Results from our laboratory showed that TH phosphorylation at serine 31 and serine 40 was increased during naloxone-induced morphine withdrawal in rats, a fact that, together with the existence of enhanced NA turnover in the NTS during morphine withdrawal, suggests that TH regulates noradrenergic activity [24, 31, 48–50]. Besides, the blockade of GR with mifepristone, selective antagonist of GR, significantly attenuated the phosphorylation at serine 31, but not at serine 40 in the NTS during morphine withdrawal [48, 50], different to the results after blockade of MR with spironolactone. Pretreatment with this antagonist decreased phosphorylation of serine 31 in the NTS but not significantly [49, 50] (**Figure 3**). These results would suggest that enhanced glucocorticoid release during morphine withdrawal results in TH phosphorylation at serine 31, consequently, also in enhanced TH activity, and finally in higher catecholamine levels in the PVN, innervated by noradrenergic system.

### **Figure 3.**

*Opioids - From Analgesic Use to Addiction*

**3. Role of glucocorticoids in addiction**

Glucocorticoids are the final step of HPA axis, and their release takes place in response to stressful situations, becoming this activation one of the main mechanisms of adaption to stress [40]. Glucocorticoids make their function by interacting

*Representation of the extended amygdala. The extrahypothalamic brain stress system or extended amygdala is shown here in a scheme with its main nuclei: BNST, CeA, and NAc. Noradrenergic innervations establish a feedforward loop between CRF and NA, which remains crucial for the development of drug addiction and relapses. Besides, there is dopaminergic innervation from ventral tegmental area to different nuclei establishing a relationship between NA system, DA system, and the brain stress system (hypothalamic and* 

Whereas MR are located in limbic areas of the brain such as amygdala and also in the PVN or the locus coeruleus (LC) [42], GR have a more heterogeneous localization, with deep presence in the PVN, amygdala, or the hippocampus. MR have higher affinity for corticosterone than GR, but GR are activated when there are stressful facts differently to MR, which are important at basal levels. Both receptors have presence in the NTS, making this nucleus to be important in glucocorticoid effects [43]. Previous research has shown that MR blockade decreases self-adminis-

Moreover, stress affects GR, which are located through the dopaminergic pathways enhancing HPA axis and dopaminergic activity. In fact, glucocorticoids have been suggested to interact with a GRE site located in TH, resulting in the upregulation of TH synthesis and, finally, increasing DA release in the NAc [45]. Therefore, individuals with higher HPA axis activity would be more vulnerable to develop drug

tration of cocaine, suggesting a role for these receptors in addiction [44].

**4. Involvement of GR and MR in TH activity and phosphorylation** 

The regulation in the biosynthesis of catecholamines by TH depends on its phosphorylation at serine 31 and serine 40. This has been proposed to be triggered by stressful situations considering that increased release of glucocorticoids results in uprising TH activity [46]. Moreover, morphine withdrawal induced by naloxone injection increased TH mRNA expression in the NTS and TH activity in the PVN [47]. Therefore, it was critical to elucidate if blocking GR and MR with mifepristone and

with two classes of receptors: MR or type I and GR or type II [41].

**44**

addiction [5].

**Figure 2.**

*extrahypothalamic).*

**in the NTS**

*Antagonization of TH phosphorylation at serine 31 by mifepristone (GR antagonist). Mifepristone (C) but not spironolactone (A) antagonized naloxone-induced morphine-withdrawal phosphorylation of TH at serine 31 in the NTS. Representative immunoblots of THpSer31 (A, C) and THpSer40 (B, D) in the NTS tissues isolated from placebo and morphine-dependent rats 60 min after administration of naloxone and the respective antagonist [mifepristone (C, D) or spironolactone (A, B)] or saline. Data represent the optical density of immunoreactive bands expressed as a percentage (%) of the mean ± SEM of placebo control band \* P < 0.05 versus placebo + vehicle + naloxone; \*\*P < 0.01 versus placebo + vehicle + naloxone; # P < 0.05 versus morphine + vehicle + naloxone; ++P < 0.01 versus placebo + spironolactone+ naloxone; +++P < 0.001 versus placebo + spironolactone + naloxone.*

### **5. Role of GR and MR in the activation of ERK pathway and CREB (via phosphorylation) in the NTS**

Different studies have proposed the importance of ERK pathway in drug addiction, particularly, during morphine withdrawal [51, 52]. Protein Kinase C (PKC) regulates this pathway activated by the phosphorylation of ERKs [50, 52]. It is important to highlight that previous research has shown that ERK has a main role in the phosphorylation of TH at serine 31 in the NTS [53], supporting a synergic cooperation between the brain stress system, the noradrenergic system, and this pathway. GR but not MR blockade significantly decreased the enhanced activity (via phosphorylation) seen in pERK1 and pERK2 during morphine withdrawal in rats, supporting a role for glucocorticoids in activation of ERK pathway (**Figure 4**).

On the other hand, it is known that CREB has a main role in addiction to drugs of abuse as a transcription factor [54]. Nevertheless, CREB is the final step of protein kinase A (PKA) signaling pathway, although PKC pathway has been also proposed to be mediating its activation in the NTS [16]. As it happens with ERK,

### **Figure 4.**

*Antagonization of ERK 1 and ERK 2 phosphorylation by mifepristone (GR antagonist). Mifepristone (A, C) but not spironolactone (B, D) antagonized naloxone-induced morphine-withdrawal phosphorylation of ERK 1 and ERK 2 in the NTS. Representative immunoblots of ERK 1 (A, B) and ERK 2 (C, D) in the NTS tissues isolated from placebo and morphine-dependent rats 60 min after administration of naloxone and the respective antagonist [mifepristone (A, C) or spironolactone (B, D)] or saline. Data represent the optical density of immunoreactive bands expressed as a percentage (%) of the mean ± SEM of placebo control band. \* P < 0.05 versus placebo + vehicle+ naloxone; \*\*P < 0.01 versus placebo + vehicle + naloxone; \* P < 0.05 versus placebo + vehicle + naloxone ##P < 0.01 versus morphine + vehicle + naloxone; ###P < 0.001 versus morphine + vehicle + naloxone.*

**47**

*Role of Glucocorticoid Receptor in the Relation between Stress and Opiate Addiction*

CREB is activated via phosphorylation, and it has been shown to be enhanced in the NTS during morphine withdrawal [16, 50]. Once again, GR but not MR blockade significantly decreased the phosphorylation of CREB seen during morphine withdrawal [50] (**Figure 5**). Therefore, GR would be implicated in CREB activation

*Antagonization of CREB phosphorylation by mifepristone (GR antagonist). Mifepristone (A) but not spironolactone (B) antagonized naloxone-induced morphine-withdrawal phosphorylation of CREB in the NTS. Representative immunoblots of pCREB in the NTS tissues isolated from placebo and morphinedependent rats 60 min after administration of naloxone and the respective antagonist mifepristone (A) or spironolactone (B) or saline. Data represent the optical density of immunoreactive bands expressed as a percentage (%) of the mean ± SEM of placebo control band. \*P < 0.05 versus placebo + vehicle + naloxone; ##P < 0.01 versus morphine + vehicle + naloxone.*

Previous research has shown that CRE (binding site for CREB) and GRE (binding site for GR) are present in the gene promoters that regulate activity of TH [55], setting a relationship between NA system, the HPA axis and the extended amygdala, and finally, CREB. In contrast, little was known about the mechanisms underlying this regulation. This review suggests that stressful situations as naloxone-induced morphine withdrawal would result in glucocorticoid release which would activate GR. Immediately, GR would produce an activation of PKC signaling pathway that would regulate ERK pathway and CREB activation (via phosphorylation) in the NTS. Finally, TH activity would be enhanced in the NTS through the activation of different sites as CRE or GRE resulting in catecholamine release in the PVN, supporting a main role for glucocorticoids and the GR in drug addiction.

This research was supported by a grant from the Ministerio de Economía, Industria y Competitividad (SAF2017-85679-R) and a grant from Fundación Séneca-Agencia de Ciencia y Tecnología de la Región de Murcia (20847/PI/18).

*DOI: http://dx.doi.org/10.5772/intechopen.90839*

during morphine withdrawal in the NTS.

**6. Conclusion**

**Figure 5.**

**Acknowledgements**

**Conflict of interest**

The authors declare no conflict of interest.

*Role of Glucocorticoid Receptor in the Relation between Stress and Opiate Addiction DOI: http://dx.doi.org/10.5772/intechopen.90839*

### **Figure 5.**

*Opioids - From Analgesic Use to Addiction*

**(via phosphorylation) in the NTS**

**5. Role of GR and MR in the activation of ERK pathway and CREB** 

of abuse as a transcription factor [54]. Nevertheless, CREB is the final step of protein kinase A (PKA) signaling pathway, although PKC pathway has been also proposed to be mediating its activation in the NTS [16]. As it happens with ERK,

*Antagonization of ERK 1 and ERK 2 phosphorylation by mifepristone (GR antagonist). Mifepristone (A, C) but not spironolactone (B, D) antagonized naloxone-induced morphine-withdrawal phosphorylation of ERK 1 and ERK 2 in the NTS. Representative immunoblots of ERK 1 (A, B) and ERK 2 (C, D) in the NTS tissues isolated from placebo and morphine-dependent rats 60 min after administration of naloxone and the respective antagonist [mifepristone (A, C) or spironolactone (B, D)] or saline. Data represent the optical density of immunoreactive bands expressed as a percentage (%) of the mean ± SEM of placebo control band.* 

*placebo + vehicle + naloxone ##P < 0.01 versus morphine + vehicle + naloxone; ###P < 0.001 versus morphine +* 

*P < 0.05 versus* 

*P < 0.05 versus placebo + vehicle+ naloxone; \*\*P < 0.01 versus placebo + vehicle + naloxone; \**

Different studies have proposed the importance of ERK pathway in drug addiction, particularly, during morphine withdrawal [51, 52]. Protein Kinase C (PKC) regulates this pathway activated by the phosphorylation of ERKs [50, 52]. It is important to highlight that previous research has shown that ERK has a main role in the phosphorylation of TH at serine 31 in the NTS [53], supporting a synergic cooperation between the brain stress system, the noradrenergic system, and this pathway. GR but not MR blockade significantly decreased the enhanced activity (via phosphorylation) seen in pERK1 and pERK2 during morphine withdrawal in rats, supporting a role for glucocorticoids in activation of ERK pathway (**Figure 4**). On the other hand, it is known that CREB has a main role in addiction to drugs

**46**

*\**

**Figure 4.**

*vehicle + naloxone.*

*Antagonization of CREB phosphorylation by mifepristone (GR antagonist). Mifepristone (A) but not spironolactone (B) antagonized naloxone-induced morphine-withdrawal phosphorylation of CREB in the NTS. Representative immunoblots of pCREB in the NTS tissues isolated from placebo and morphinedependent rats 60 min after administration of naloxone and the respective antagonist mifepristone (A) or spironolactone (B) or saline. Data represent the optical density of immunoreactive bands expressed as a percentage (%) of the mean ± SEM of placebo control band. \*P < 0.05 versus placebo + vehicle + naloxone; ##P < 0.01 versus morphine + vehicle + naloxone.*

CREB is activated via phosphorylation, and it has been shown to be enhanced in the NTS during morphine withdrawal [16, 50]. Once again, GR but not MR blockade significantly decreased the phosphorylation of CREB seen during morphine withdrawal [50] (**Figure 5**). Therefore, GR would be implicated in CREB activation during morphine withdrawal in the NTS.

### **6. Conclusion**

Previous research has shown that CRE (binding site for CREB) and GRE (binding site for GR) are present in the gene promoters that regulate activity of TH [55], setting a relationship between NA system, the HPA axis and the extended amygdala, and finally, CREB. In contrast, little was known about the mechanisms underlying this regulation. This review suggests that stressful situations as naloxone-induced morphine withdrawal would result in glucocorticoid release which would activate GR. Immediately, GR would produce an activation of PKC signaling pathway that would regulate ERK pathway and CREB activation (via phosphorylation) in the NTS. Finally, TH activity would be enhanced in the NTS through the activation of different sites as CRE or GRE resulting in catecholamine release in the PVN, supporting a main role for glucocorticoids and the GR in drug addiction.

### **Acknowledgements**

This research was supported by a grant from the Ministerio de Economía, Industria y Competitividad (SAF2017-85679-R) and a grant from Fundación Séneca-Agencia de Ciencia y Tecnología de la Región de Murcia (20847/PI/18).

### **Conflict of interest**

The authors declare no conflict of interest.

*Opioids - From Analgesic Use to Addiction*

### **Author details**

Javier Navarro-Zaragoza\*, María Victoria Milanés and María Luisa Laorden Faculty of Medicine, Department of Pharmacology, University of Murcia, Spain

\*Address all correspondence to: jnavarrozaragoza@um.es

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**49**

*Role of Glucocorticoid Receptor in the Relation between Stress and Opiate Addiction*

[12] Koob GF. Brain stress systems in the amygdala and addiction. Brain

Research. 2009;**1293**:61-75

2000;**403**:430-434

Sciences. 1999;**897**:27-45

Neuroscience. 2005;**8**:212-219

Morphine withdrawal regulates phosphorylation of cAMP response element binding protein (CREB) through PKC in the nucleus tractus solitarius-A2 catecholaminergic neurons. Journal of Neurochemistry. 2009;**110**:1422-1432

[17] Goodman A. Neurobiology of addiction. An integrated review. Biochemical Pharmacology.

[18] Koob GF, Le Moal M. Neurobiological mechanisms for opponent motivational processes in addiction. Philosophical Transactions of the Royal Society B: Biological Sciences. 2008;**363**:3113-3123

[19] Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues in Clinical Neuroscience.

[20] Lowery EG, Spanos M, Navarro M, Lyons AM, Hodge CW, Thiele TE. CRF-1

antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/6J mice independent of the

2008;**75**:266-322

2006;**8**:383-395

[13] Delfs JM, Zhu Y, Druhan JP, Aston-Jones G. Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion. Nature.

[14] Koob GF. Stress, corticotropinreleasing factor, and drug addiction. Annals of the New York Academy of

[15] Lu L, Hope BT, Dempsey J, Liu SY, Bossert JM, Shaham Y. Central amygdala ERK signalling pathway is critical to incubation of cocaine craving. Nature

[16] Martín F, Laorden ML, Milanes MV.

*DOI: http://dx.doi.org/10.5772/intechopen.90839*

[1] Koob GF, Schulkin J. Addiction and stress: An allostatic view. Neuroscience and Biobehavioral Reviews. 2019;**106**:

[2] Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology.

[3] Robinson TE, Berridge KC. Addiction. Annual Review of Psychology. 2003;**54**:

[5] Uhart M, Wand GS. Stress, alcohol and drug interaction: An update of human research. Addiction Biology.

[6] Kalivas PW, O'Brien C. Drug addiction as a pathology of staged neuroplasticity.

Neuropsychopharmacology.

Pharmacology. 2007;**7**:69-76

[9] Robbins TW, Everitt BJ. Neurobehavioural mechanisms of reward and motivation. Current Opinion

in Neurobiology. 1996;**6**:228-236

[11] Koob GF, Simon EJ. The

[10] Hyman SE, Malenka RC. Addiction and the brain: The neurobiology of compulsion and its persistence. Nature Reviews. Neuroscience. 2001;**2**:695-703

neurobiology of addiction: Where we have been and where we are going. Journal of Drug Issues. 2009;**39**:115-132

[7] Di Chiara G, Bassareo V. Reward system and addiction: What dopamine does and doesn't do. Current Opinion in

[8] Wise RA. Neurobiology of addiction. Current Opinion in Neurobiology.

[4] Koob G, Kreek MJ. Stress, dysregulation of drug reward pathways, and the transition to drug dependence. The American Journal of Psychiatry. 2007;**164**:1149-1159

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2010;**35**:217-238

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2008;**33**:166-180

1996;**6**:243-251

*Role of Glucocorticoid Receptor in the Relation between Stress and Opiate Addiction DOI: http://dx.doi.org/10.5772/intechopen.90839*

### **References**

*Opioids - From Analgesic Use to Addiction*

**48**

**Author details**

Javier Navarro-Zaragoza\*, María Victoria Milanés and María Luisa Laorden Faculty of Medicine, Department of Pharmacology, University of Murcia, Spain

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: jnavarrozaragoza@um.es

provided the original work is properly cited.

[1] Koob GF, Schulkin J. Addiction and stress: An allostatic view. Neuroscience and Biobehavioral Reviews. 2019;**106**: 245-262

[2] Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;**35**:217-238

[3] Robinson TE, Berridge KC. Addiction. Annual Review of Psychology. 2003;**54**: 25-53

[4] Koob G, Kreek MJ. Stress, dysregulation of drug reward pathways, and the transition to drug dependence. The American Journal of Psychiatry. 2007;**164**:1149-1159

[5] Uhart M, Wand GS. Stress, alcohol and drug interaction: An update of human research. Addiction Biology. 2009;**14**:43-64

[6] Kalivas PW, O'Brien C. Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology. 2008;**33**:166-180

[7] Di Chiara G, Bassareo V. Reward system and addiction: What dopamine does and doesn't do. Current Opinion in Pharmacology. 2007;**7**:69-76

[8] Wise RA. Neurobiology of addiction. Current Opinion in Neurobiology. 1996;**6**:243-251

[9] Robbins TW, Everitt BJ. Neurobehavioural mechanisms of reward and motivation. Current Opinion in Neurobiology. 1996;**6**:228-236

[10] Hyman SE, Malenka RC. Addiction and the brain: The neurobiology of compulsion and its persistence. Nature Reviews. Neuroscience. 2001;**2**:695-703

[11] Koob GF, Simon EJ. The neurobiology of addiction: Where we have been and where we are going. Journal of Drug Issues. 2009;**39**:115-132 [12] Koob GF. Brain stress systems in the amygdala and addiction. Brain Research. 2009;**1293**:61-75

[13] Delfs JM, Zhu Y, Druhan JP, Aston-Jones G. Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion. Nature. 2000;**403**:430-434

[14] Koob GF. Stress, corticotropinreleasing factor, and drug addiction. Annals of the New York Academy of Sciences. 1999;**897**:27-45

[15] Lu L, Hope BT, Dempsey J, Liu SY, Bossert JM, Shaham Y. Central amygdala ERK signalling pathway is critical to incubation of cocaine craving. Nature Neuroscience. 2005;**8**:212-219

[16] Martín F, Laorden ML, Milanes MV. Morphine withdrawal regulates phosphorylation of cAMP response element binding protein (CREB) through PKC in the nucleus tractus solitarius-A2 catecholaminergic neurons. Journal of Neurochemistry. 2009;**110**:1422-1432

[17] Goodman A. Neurobiology of addiction. An integrated review. Biochemical Pharmacology. 2008;**75**:266-322

[18] Koob GF, Le Moal M. Neurobiological mechanisms for opponent motivational processes in addiction. Philosophical Transactions of the Royal Society B: Biological Sciences. 2008;**363**:3113-3123

[19] Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues in Clinical Neuroscience. 2006;**8**:383-395

[20] Lowery EG, Spanos M, Navarro M, Lyons AM, Hodge CW, Thiele TE. CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/6J mice independent of the

HPA axis. Neuropsychopharmacology. 2010;**35**:1241-1252

[21] Lowery EG, Thiele TE. Pre-clinical evidence that corticotropin-releasing factor (CRF) receptor antagonists are promising targets for pharmacological treatment of alcoholism. CNS and Neurological Disorders Drug Targets. 2010;**9**:77-86

[22] Shalev U, Erb S, Shaham Y. Role of CRF and other neuropeptides in stressinduced reinstatement of drug seeking. Brain Research. 2010;**1314**:15-28

[23] Koob GF. The dark of emotion: The addiction perspective. European Journal of Pharmacology. 2015;**753**:73-87

[24] Navarro-Zaragoza J, Núñez C, Ruiz-Medina J, Laorden ML, Valverde O, Milanés MV. CRF(2) mediates the increased noradrenergic activity in the hypothalamic paraventricular nucleus and the negative state of morphine withdrawal in rats. British Journal of Pharmacology. 2011;**162**:851-862

[25] Sinha R. How does stress increase risk of drug abuse and relapse? Psychopharmacology. 2001;**158**:343-359

[26] Erb S, Shaham Y, Stewart J. Stress reinstates cocaine seeking behaviour after prolonged extinction and a drug-free period. Psychopharmacology. 1996;**128**:408-412

[27] Volkow ND, Michaelides M, Baler R. The neuroscience of drug reward and addiction. Physiological Reviews. 2019;**99**:2115-2140

[28] Koob GF, Le Moal M. Addiction and the brain antireward system. Annual Review of Physiology. 2008;**59**:29-53

[29] Edwards S, Koob GF. Experimental psychiatric illness and drug abuse models: From human to animal, an overview. Methods in Molecular Biology. 2012;**829**:31-48

[30] Daviu N, Bruchas MR, Moghaddam B, Sandi C, Beyeler A. Neurobiological links between stress and anxiety. Neurobiol Stress. 2019;**11**:100191

[31] Navarro-Zaragoza J, Núñez C, Laorden ML, Milanes MV. Effects of corticotropin-releasing factor receptor-1 (CRF1R) antagonists on the brain stress system responses to morphine withdrawal. Molecular Pharmacology. 2010;**77**:864-873

[32] Jiang Z, Shivakumar R, Justice NJ. CRF signaling between neurons in the paraventricular nucleus of the hypothalamus (PVN) coordinates stress responses. Neurobiol Stress. 2019;**11**:100192

[33] Bale TL, Vale WW. CRF and CRF receptors: Role in stress responsivity and other behaviors. Annual Review of Pharmacology and Toxicology. 2004;**44**:525-557

[34] Orozco-Cabal L, Pollandt S, Liu J, Shinnick-Gallagher P, Gallagher JP. Regulation of synaptic transmission by CRF receptors. Reviews in the Neurosciences. 2006;**17**:279-307

[35] Lavicky J, Dunn AJ. Corticotropinreleasing factor stimulates catecholamine release in hypothalamus and prefrontal cortex in freely moving rats as assessed by microdialysis. Journal of Neurochemistry. 1993;**60**:602-612

[36] Martin F, Nunez C, Marin MT, Laorden ML, Kovacs KJ, Milanes MV. Involvement of noradrenergic transmission in the PVN on CREB activation, TORC1 levels, and pituitaryadrenal Axis activity during morphine withdrawal. PLoS One. 2012;**7**:e31119, 57

[37] Delfs JM, Zhu Y, Druhan JP, Aston-Jones GS. Origin of noradrenergic afferents to the shell subregion of the nucleus accumbens: Anterograde and retrograde tract-tracing studies in the rat. Brain Research. 1998;**806**:127-140

**51**

*Role of Glucocorticoid Receptor in the Relation between Stress and Opiate Addiction*

[46] Hagerty T, Fernandez E, Lynch K, Wang SS, Morgan WW,

glucocorticoid-responsive element with regulatory sequences in the promoter region of the mouse tyrosine hydroxylase gene. Journal of Neurochemistry. 2001;**78**:1379-1388

[47] Benavides M, Laorden ML, García-Borrón JC, Milanés MV. Regulation of tyrosine hydroxilase levels and activity and Fos expression during opioid withdrawal in the hypothalamic PVN and medulla

oblongata catecholaminergic cell groups innervating the PVN. The European Journal of Neuroscience. 2003;**17**:103-112

[48] Navarro-Zaragoza J, Hidalgo JM, Laorden ML, Milanés MV. Glucocorticoids participate in the opiate-withdrawal-induced stimulation of rats NTS noradrenergic activity and in the somatic signs of morphine withdrawal. British Journal of Pharmacology. 2012;**166**:2136-2147

[49] Navarro-Zaragoza J, Laorden ML, Milanés MV. Spironolactone decreases the somatic signs of opiate withdrawal by blocking the mineralocorticoid receptors (MR). Toxicology. 2014;**326**:36-43

[50] Navarro-Zaragoza J, Laorden ML, Milanés MV. Glucocorticoid receptor but not mineralocorticoid receptor mediates the activation of ERK pathway and CREB during morphine withdrawal. Addiction Biology.

[51] Cao JL, He JH, Ding HL, Zeng YM. Activation of the spinal ERK signalling

[52] Almela P, Milanés MV, Laorden ML. Activation of the ERK signalling pathway contributes to the adaptive changes in rat hearts during naloxoneinduced morphine withdrawal.

pathways contributes naloxoneprecipitated withdrawal in morphine dependents rats. Pain. 2005;**118**:336-349

2017;**22**:342-353

Strong R. Interaction of a

*DOI: http://dx.doi.org/10.5772/intechopen.90839*

[39] Barrot M, Abrous DN, Marinelli M, Rouge-Pont F, Le Moal M, Piazza PV. Influence of glucocorticoids on dopaminergic transmission in the rat dorsolateral striatum. The European Journal of Neuroscience.

[41] Noguchi T, Makino S, Matsumoto R, Nakayama S, Nishiyama M, Terada Y, et al. Regulation of Glucocorticoid Receptor transcription and nuclear translocation during single and repeated immobilization stress. Endocrinology.

[42] Marinelli PW, Harding S, Funk D, Juzytsch W, Le AD. The influence of stress on the alcohol deprivation effect and of stress-associated cues on reinstatement in the rat. Alcoholism, Clinical and Experimental Research.

[43] Joels M, Baram TZ. The neurosymphony of stress. Nature Reviews. Neuroscience. 2009;**10**:459-484

[44] Fiancette JF, Balado E, Piazza PV, Deroche-Gamonet V. Mifepristone and spironolactone differently alter cocaine intravenous self-administration and cocaine-induced locomotion in C57BL/6J mice. Addiction Biology. 2010;**15**:81-87

Glucocorticoids as a biological substrate

pathophysiological implications. Brain Research Reviews. 1997;**25**:359-372

[45] Piazza PV, Le Moal M.

of reward: Physiological and

2001;**13**:812-818

[40] Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC, et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nature

Genetics. 1999;**23**:99-103

2010;**151**:4344-4355

2006;**30**:27

[38] de Jong IME, Steenbergen PJ, de Kloet ER. Behavioral sensitization to cocaine: Cooperation between glucocorticoids and epinephrine. Psychopharmacology. 2009;**204**:693-703 *Role of Glucocorticoid Receptor in the Relation between Stress and Opiate Addiction DOI: http://dx.doi.org/10.5772/intechopen.90839*

[38] de Jong IME, Steenbergen PJ, de Kloet ER. Behavioral sensitization to cocaine: Cooperation between glucocorticoids and epinephrine. Psychopharmacology. 2009;**204**:693-703

*Opioids - From Analgesic Use to Addiction*

2010;**35**:1241-1252

2010;**9**:77-86

HPA axis. Neuropsychopharmacology.

[30] Daviu N, Bruchas MR,

2010;**77**:864-873

2019;**11**:100192

2004;**44**:525-557

Moghaddam B, Sandi C, Beyeler A. Neurobiological links between stress and anxiety. Neurobiol Stress. 2019;**11**:100191

[31] Navarro-Zaragoza J, Núñez C, Laorden ML, Milanes MV. Effects of corticotropin-releasing factor receptor-1 (CRF1R) antagonists on the brain stress system responses to morphine withdrawal. Molecular Pharmacology.

[32] Jiang Z, Shivakumar R, Justice NJ. CRF signaling between neurons in the paraventricular nucleus of the hypothalamus (PVN) coordinates stress responses. Neurobiol Stress.

[33] Bale TL, Vale WW. CRF and CRF receptors: Role in stress responsivity and other behaviors. Annual Review of Pharmacology and Toxicology.

[34] Orozco-Cabal L, Pollandt S, Liu J, Shinnick-Gallagher P, Gallagher JP. Regulation of synaptic transmission by CRF receptors. Reviews in the Neurosciences. 2006;**17**:279-307

[35] Lavicky J, Dunn AJ. Corticotropinreleasing factor stimulates catecholamine release in hypothalamus and prefrontal

cortex in freely moving rats as assessed by microdialysis. Journal of Neurochemistry. 1993;**60**:602-612

[36] Martin F, Nunez C, Marin MT, Laorden ML, Kovacs KJ, Milanes MV. Involvement of noradrenergic transmission in the PVN on CREB activation, TORC1 levels, and pituitaryadrenal Axis activity during morphine withdrawal. PLoS One. 2012;**7**:e31119, 57

[37] Delfs JM, Zhu Y, Druhan JP,

Aston-Jones GS. Origin of noradrenergic afferents to the shell subregion of the nucleus accumbens: Anterograde and retrograde tract-tracing studies in the rat. Brain Research. 1998;**806**:127-140

[21] Lowery EG, Thiele TE. Pre-clinical evidence that corticotropin-releasing factor (CRF) receptor antagonists are promising targets for pharmacological treatment of alcoholism. CNS and Neurological Disorders Drug Targets.

[22] Shalev U, Erb S, Shaham Y. Role of CRF and other neuropeptides in stressinduced reinstatement of drug seeking.

[23] Koob GF. The dark of emotion: The addiction perspective. European Journal

Brain Research. 2010;**1314**:15-28

of Pharmacology. 2015;**753**:73-87

[24] Navarro-Zaragoza J, Núñez C, Ruiz-Medina J, Laorden ML, Valverde O, Milanés MV. CRF(2) mediates the increased noradrenergic activity in the hypothalamic paraventricular nucleus and the negative state of morphine withdrawal in rats. British Journal of Pharmacology. 2011;**162**:851-862

[25] Sinha R. How does stress increase risk of drug abuse and relapse?

Psychopharmacology. 2001;**158**:343-359

[26] Erb S, Shaham Y, Stewart J. Stress reinstates cocaine seeking behaviour after prolonged extinction and a drug-free period. Psychopharmacology.

[27] Volkow ND, Michaelides M, Baler R. The neuroscience of drug reward and addiction. Physiological

[28] Koob GF, Le Moal M. Addiction and the brain antireward system. Annual Review of Physiology. 2008;**59**:29-53

[29] Edwards S, Koob GF. Experimental psychiatric illness and drug abuse models: From human to animal, an overview. Methods in Molecular Biology.

Reviews. 2019;**99**:2115-2140

1996;**128**:408-412

**50**

2012;**829**:31-48

[39] Barrot M, Abrous DN, Marinelli M, Rouge-Pont F, Le Moal M, Piazza PV. Influence of glucocorticoids on dopaminergic transmission in the rat dorsolateral striatum. The European Journal of Neuroscience. 2001;**13**:812-818

[40] Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC, et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nature Genetics. 1999;**23**:99-103

[41] Noguchi T, Makino S, Matsumoto R, Nakayama S, Nishiyama M, Terada Y, et al. Regulation of Glucocorticoid Receptor transcription and nuclear translocation during single and repeated immobilization stress. Endocrinology. 2010;**151**:4344-4355

[42] Marinelli PW, Harding S, Funk D, Juzytsch W, Le AD. The influence of stress on the alcohol deprivation effect and of stress-associated cues on reinstatement in the rat. Alcoholism, Clinical and Experimental Research. 2006;**30**:27

[43] Joels M, Baram TZ. The neurosymphony of stress. Nature Reviews. Neuroscience. 2009;**10**:459-484

[44] Fiancette JF, Balado E, Piazza PV, Deroche-Gamonet V. Mifepristone and spironolactone differently alter cocaine intravenous self-administration and cocaine-induced locomotion in C57BL/6J mice. Addiction Biology. 2010;**15**:81-87

[45] Piazza PV, Le Moal M. Glucocorticoids as a biological substrate of reward: Physiological and pathophysiological implications. Brain Research Reviews. 1997;**25**:359-372

[46] Hagerty T, Fernandez E, Lynch K, Wang SS, Morgan WW, Strong R. Interaction of a glucocorticoid-responsive element with regulatory sequences in the promoter region of the mouse tyrosine hydroxylase gene. Journal of Neurochemistry. 2001;**78**:1379-1388

[47] Benavides M, Laorden ML, García-Borrón JC, Milanés MV. Regulation of tyrosine hydroxilase levels and activity and Fos expression during opioid withdrawal in the hypothalamic PVN and medulla oblongata catecholaminergic cell groups innervating the PVN. The European Journal of Neuroscience. 2003;**17**:103-112

[48] Navarro-Zaragoza J, Hidalgo JM, Laorden ML, Milanés MV. Glucocorticoids participate in the opiate-withdrawal-induced stimulation of rats NTS noradrenergic activity and in the somatic signs of morphine withdrawal. British Journal of Pharmacology. 2012;**166**:2136-2147

[49] Navarro-Zaragoza J, Laorden ML, Milanés MV. Spironolactone decreases the somatic signs of opiate withdrawal by blocking the mineralocorticoid receptors (MR). Toxicology. 2014;**326**:36-43

[50] Navarro-Zaragoza J, Laorden ML, Milanés MV. Glucocorticoid receptor but not mineralocorticoid receptor mediates the activation of ERK pathway and CREB during morphine withdrawal. Addiction Biology. 2017;**22**:342-353

[51] Cao JL, He JH, Ding HL, Zeng YM. Activation of the spinal ERK signalling pathways contributes naloxoneprecipitated withdrawal in morphine dependents rats. Pain. 2005;**118**:336-349

[52] Almela P, Milanés MV, Laorden ML. Activation of the ERK signalling pathway contributes to the adaptive changes in rat hearts during naloxoneinduced morphine withdrawal.

British Journal of Pharmacology. 2007;**151**:787-797

[53] Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki E, Dickson PW. Tyrosine hydroxylase phosphorylation: Regulation and consequences. Journal of Neurochemistry. 2004;**91**:1025-1043

[54] Nestler EJ. Celullar basis of memory for addiction. Dialogues in Clinical Neuroscience. 2013;**15**(4):431-443

[55] Rani CSS, Elango N, Wang S, Kobayashi K, Strong R. Identification of an activator protein-1-like sequence as the glucocorticoid response element in the rat tyrosine hydroxylase gene. Molecular Pharmacology. 2009;**75**:589-598

**53**

**Chapter 5**

Corticotrophin-Releasing Factor

(CRF) through CRF1 Receptor

Morphine-Related Positive and

Different studies have elucidated the mechanisms underlying the formation and expression of drug-related cue memories; corticotrophin-releasing factor (CRF) plays a critical role in reward- and aversion-driven associative learning. In the present chapter, we have evaluated whether CP-154,526, a selective CRF1 receptor (CRF1R) antagonist, or genetic deletion of CRF1R (KO mice) have comparable effects on conditioned place preference (CPP) and conditioned place aversion (CPA) learning. We also investigated CP-154,526 effects on morphine-induced CPP activation of CRF, CREB phosphorylation, and thioredoxin (Trx1) expression in dentate gyrus (DG), a brain region involved in memory consolidation, and the role of hypothalamic-pituitary-adrenocortical (HPA) axis in CPA expression and extinction. The CRF1R antagonist abolished the acquisition of morphine CPP, Trx-1 and BDNF increased expression, and pCREB/Trx-1 co-localization in the DG. The increase in adrenocorticotropic hormone (ACTH) plasma levels observed after CPA expression was attenuated in CRF1R KO mice, suggesting a role of HPA axis in aversive memories. Altogether, these results suggest a critical role of CRF, through CRF1R, in molecular changes involved in memory formation and consolidation and

may facilitate the development of effective treatments for opioid addiction.

of memory is considered to be crucial for the treatment of drug addiction.

**Keywords:** conditioned place preference, conditioned place aversion, morphine,

Drug addiction is a chronic brain disease with a high rate of relapse [1–3]. Despite years of abstinence from drugs, relapse can occur when addicts encounter cues, including people or places, associated with their prior drug use [4]. Drug-associated memory can persist throughout the lifetime of a patient; therefore, the elimination of this kind

Facilitates the Expression of

Aversive Memory in Mice

*Pilar Almela, Juan A. García-Carmona,* 

*and María L. Laorden*

hippocampus, CRF, HPA axis

**1. Introduction**

**Abstract**

*Elena Martínez-Laorden, María V. Milanés* 

### **Chapter 5**

*Opioids - From Analgesic Use to Addiction*

British Journal of Pharmacology.

[53] Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki E, Dickson PW. Tyrosine hydroxylase phosphorylation: Regulation and consequences. Journal of Neurochemistry. 2004;**91**:1025-1043

[54] Nestler EJ. Celullar basis of memory for addiction. Dialogues in Clinical Neuroscience. 2013;**15**(4):431-443

[55] Rani CSS, Elango N, Wang S, Kobayashi K, Strong R. Identification of an activator protein-1-like sequence as the glucocorticoid response element

in the rat tyrosine hydroxylase gene. Molecular Pharmacology.

2009;**75**:589-598

2007;**151**:787-797

**52**

## Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression of Morphine-Related Positive and Aversive Memory in Mice

*Pilar Almela, Juan A. García-Carmona, Elena Martínez-Laorden, María V. Milanés and María L. Laorden*

### **Abstract**

Different studies have elucidated the mechanisms underlying the formation and expression of drug-related cue memories; corticotrophin-releasing factor (CRF) plays a critical role in reward- and aversion-driven associative learning. In the present chapter, we have evaluated whether CP-154,526, a selective CRF1 receptor (CRF1R) antagonist, or genetic deletion of CRF1R (KO mice) have comparable effects on conditioned place preference (CPP) and conditioned place aversion (CPA) learning. We also investigated CP-154,526 effects on morphine-induced CPP activation of CRF, CREB phosphorylation, and thioredoxin (Trx1) expression in dentate gyrus (DG), a brain region involved in memory consolidation, and the role of hypothalamic-pituitary-adrenocortical (HPA) axis in CPA expression and extinction. The CRF1R antagonist abolished the acquisition of morphine CPP, Trx-1 and BDNF increased expression, and pCREB/Trx-1 co-localization in the DG. The increase in adrenocorticotropic hormone (ACTH) plasma levels observed after CPA expression was attenuated in CRF1R KO mice, suggesting a role of HPA axis in aversive memories. Altogether, these results suggest a critical role of CRF, through CRF1R, in molecular changes involved in memory formation and consolidation and may facilitate the development of effective treatments for opioid addiction.

**Keywords:** conditioned place preference, conditioned place aversion, morphine, hippocampus, CRF, HPA axis

### **1. Introduction**

Drug addiction is a chronic brain disease with a high rate of relapse [1–3]. Despite years of abstinence from drugs, relapse can occur when addicts encounter cues, including people or places, associated with their prior drug use [4]. Drug-associated memory can persist throughout the lifetime of a patient; therefore, the elimination of this kind of memory is considered to be crucial for the treatment of drug addiction.

In organism and human models, drug reward can be assessed using a Pavlovian conditioning procedure known as conditioned place preference/conditioned place aversion (CPP/CPA) [5–7]. CPP for the drug-paired environment is predicted by self-reported measures of drug liking in humans [6]. CPA for the drug-paired environment is used to infer the dysphoric properties of drugs, including opioid receptor antagonists [8]. Many neurotransmitters, neurotrophic factors, and protein kinases have been delineated in the regulation of the formation and expression of drugassociated reward memories and withdrawal-associated aversive memories [9–13].

Corticotrophin-releasing factor (CRF) in the brain plays a critical role in reward- and aversion-driven associative learning. However, it is not clear whether it does this by a common mechanism or by separated mechanisms that can be dissociated. The knowledge of these mechanisms could lead to more effective treatments for addictive processes. CRF and its CRF1 receptor (CRF1R) are widely distributed and in a highly conserved way in several brain regions, including the hippocampal formation, involved in reward reinforcement, craving and aversive effects of drug of abuse [14–17]. At the extrahypothalamic level, CRF acts as a neuroregulator of the behavioral and emotional integration of environmental and endogenous stimuli associated with drug dependence [18, 19]. In the hippocampal dentate gyrus (DG), an important brain region involved in saving similar experiences and contexts [20], CRF is released from inhibitory interneurons [21] through CRF1R [14] by environmental signals. CRF1R activation stimulates Gαs protein, promoting the induction of the protein kinase A/cAMP response element binding protein (CREB) pathway [22]. CREB activity in the brain is critical for learning and memory processes [23], and it has been reported to be involved in the expression of opioid dependence. The activation of CREB, as one of the main downstream effectors of extracellular signal-regulated kinase (ERK), accelerates the transcription of CREB-dependent genes such as the brain-derived neurotrophic factor (BDNF). With respect to hypothalamus, CRF release from paraventricular nucleus (PVN) controls the hypothalamic-pituitary-adrenal (HPA) axis responses to stress and drug addiction [24–26]. CRF neurons in the PVN and CRF fibber in DG have direct connexion with dopaminergic neurons located in the ventral tegmental area (VTA) projecting to nucleus accumbens (NAc) [27, 28].

### **2. Role of CRF in the rewarding effects of morphine**

CPP is an animal model widely used to evaluate the correlation between contexts and drugs. Different substances of abuse display differential ability to produce CPP. Opiates induce strong CPP over a wide range of experimental conditions [5]. Previous studies from our laboratory [29–32] and others [33, 34] have demonstrated that morphine administration evokes significant CPP for the drug-associated environment. Different neurobiological substrates have been involved in the rewarding properties of drugs of abuse, although the mesolimbic dopaminergic pathway has been pointed out to be the critical system for drug reward. Recently, it has been suggested that PVN may have a role in the reinforcing effects of opioids [35]. Various studies have elucidated the mechanisms underlying the formation and expression of drug-related cue memories. CRF in the brain plays a critical role in reward-driven associative learning. During the formation or consolidation process (CPP expression), the majority of the CRF-positive neurons in the PVN, central nucleus of amygdale (CeA), and bed nucleus of stria terminalis (BNST) coexpresses pCREB after morphine-induced CPP, suggesting that drug-paired context could trigger neuronal activity in the brain stress system [29]. Morphine-treated mice in their home cage do not show any changes in total CRF/CREB positive neurons, indicating

**55**

*Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression…*

**2.1 Implications of different signaling pathways in the rewarding effects** 

Hippocampus is a brain region known to participate in associative processes such as declarative memory, and PVN is an important stress area. Both structures are related with mesolimbic pathways [38]. Our group has studied the implication of different signaling pathways in both areas, because the understanding of how the formation of drug-reward memories alters the neurobiology of the hippocampal DG and PVN, and may shed light on the later and more persistent aspect of

The transcription factor CREB is critical in the conversion from short-term to long-term memory, and it is involved in the creation of long-term memory. Learning and memory and drug addiction share certain intracellular signaling pathways and depend on activation of CREB [39]. According to previous studies [40, 41], our laboratory has demonstrated that the number of pCREB positive neurons in PVN and DG is significantly increased after morphine-induced CPP expression (**Figure 1**). Since CRF1R is coupled to stimulatory G protein Gαs and can thus activate PKA and, subsequently, CREB [22], our group has investigated if CRF1R signaling is involved in CREB activity after morphine-induced CPP. Administration of the CRF1R antagonist, CP-154,526, completely revoked pCREB positive neuron enhancement induced by morphine in PVN and slightly in DG. CREB involvement in morphine dependence has been previously supported by studies demonstrating that CREB mutant mice do not respond to the reinforcing properties of morphine in a conditioned place preference paradigm [42], suggesting that specific CREB

Although it is known that CRF signaling is involved in the drug withdrawalinduced anxiogenic-like and negative behavioral response [43], no definitive data are available about the role in the positive reinforcing properties of opiates. CRFimmunoreactive fibers densely innervate many intrahypothalamic and extrahypothalamic brain areas, such as hippocampus. Besides, CRF, through CRF1R, increases neuronal activity propagation from DG, the classical hippocampal input region, to the hypothalamic structure CA1 [44]. CRF is present in GABAergic hippocampal neurons of the pyramidal cells [14]. The supramammillary (SuM) region of the hypothalamus acts a connection nucleus between limbic and hypothalamic structures involved in controlling cognitive aspects [45]. Thus, SuM sends robust and direct inputs to DG. For example, it has been shown that mild stress could activate the SuM cells that project to the hippocampus [46]. Our group has previously shown that most of the CRF positive neurons in PVN coexpresses pCREB during morphine CPP. In addition, we have observed an enhancement in CRF fibers density in DG after morphine administration. Both changes were antagonized by injection of CP-154,526 (**Figure 2**). CRF binding to CRF1R results in activation of heterotrimeric G-proteins. The physiological functions of CRF1R in the central nervous system and in the periphery have been mainly associated to an increase in intracellular cAMP levels. This is consistent with a predominant coupling to Gαs

functions are necessary for the rewarding properties of this drug.

that the exposure to drug-paired environments is necessary for CRF activation in the brain stress system [29]. Anatomical and functional studies reveal connections between CRF and the mesolimbic dopaminergic system. Thus, VTA and NAc receive CRF-positive projections from the PVN and stress extrahypothalamic areas [36, 37], which have been proposed to regulate dopamine release. The rewarding effect of morphine (CPP expression) is decreased by pretreatment with CP-154,526, a selective CRF1 antagonist, suggesting an important role of CRF/CRF1 receptor in

*DOI: http://dx.doi.org/10.5772/intechopen.80504*

memory formation and consolidation [30].

**of morphine. Role of CRF1 receptors**

addiction.

*Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression… DOI: http://dx.doi.org/10.5772/intechopen.80504*

that the exposure to drug-paired environments is necessary for CRF activation in the brain stress system [29]. Anatomical and functional studies reveal connections between CRF and the mesolimbic dopaminergic system. Thus, VTA and NAc receive CRF-positive projections from the PVN and stress extrahypothalamic areas [36, 37], which have been proposed to regulate dopamine release. The rewarding effect of morphine (CPP expression) is decreased by pretreatment with CP-154,526, a selective CRF1 antagonist, suggesting an important role of CRF/CRF1 receptor in memory formation and consolidation [30].

### **2.1 Implications of different signaling pathways in the rewarding effects of morphine. Role of CRF1 receptors**

Hippocampus is a brain region known to participate in associative processes such as declarative memory, and PVN is an important stress area. Both structures are related with mesolimbic pathways [38]. Our group has studied the implication of different signaling pathways in both areas, because the understanding of how the formation of drug-reward memories alters the neurobiology of the hippocampal DG and PVN, and may shed light on the later and more persistent aspect of addiction.

The transcription factor CREB is critical in the conversion from short-term to long-term memory, and it is involved in the creation of long-term memory. Learning and memory and drug addiction share certain intracellular signaling pathways and depend on activation of CREB [39]. According to previous studies [40, 41], our laboratory has demonstrated that the number of pCREB positive neurons in PVN and DG is significantly increased after morphine-induced CPP expression (**Figure 1**). Since CRF1R is coupled to stimulatory G protein Gαs and can thus activate PKA and, subsequently, CREB [22], our group has investigated if CRF1R signaling is involved in CREB activity after morphine-induced CPP. Administration of the CRF1R antagonist, CP-154,526, completely revoked pCREB positive neuron enhancement induced by morphine in PVN and slightly in DG. CREB involvement in morphine dependence has been previously supported by studies demonstrating that CREB mutant mice do not respond to the reinforcing properties of morphine in a conditioned place preference paradigm [42], suggesting that specific CREB functions are necessary for the rewarding properties of this drug.

Although it is known that CRF signaling is involved in the drug withdrawalinduced anxiogenic-like and negative behavioral response [43], no definitive data are available about the role in the positive reinforcing properties of opiates. CRFimmunoreactive fibers densely innervate many intrahypothalamic and extrahypothalamic brain areas, such as hippocampus. Besides, CRF, through CRF1R, increases neuronal activity propagation from DG, the classical hippocampal input region, to the hypothalamic structure CA1 [44]. CRF is present in GABAergic hippocampal neurons of the pyramidal cells [14]. The supramammillary (SuM) region of the hypothalamus acts a connection nucleus between limbic and hypothalamic structures involved in controlling cognitive aspects [45]. Thus, SuM sends robust and direct inputs to DG. For example, it has been shown that mild stress could activate the SuM cells that project to the hippocampus [46]. Our group has previously shown that most of the CRF positive neurons in PVN coexpresses pCREB during morphine CPP. In addition, we have observed an enhancement in CRF fibers density in DG after morphine administration. Both changes were antagonized by injection of CP-154,526 (**Figure 2**). CRF binding to CRF1R results in activation of heterotrimeric G-proteins. The physiological functions of CRF1R in the central nervous system and in the periphery have been mainly associated to an increase in intracellular cAMP levels. This is consistent with a predominant coupling to Gαs

*Opioids - From Analgesic Use to Addiction*

nucleus accumbens (NAc) [27, 28].

**2. Role of CRF in the rewarding effects of morphine**

CPP is an animal model widely used to evaluate the correlation between contexts

and drugs. Different substances of abuse display differential ability to produce CPP. Opiates induce strong CPP over a wide range of experimental conditions [5]. Previous studies from our laboratory [29–32] and others [33, 34] have demonstrated that morphine administration evokes significant CPP for the drug-associated environment. Different neurobiological substrates have been involved in the rewarding properties of drugs of abuse, although the mesolimbic dopaminergic pathway has been pointed out to be the critical system for drug reward. Recently, it has been suggested that PVN may have a role in the reinforcing effects of opioids [35]. Various studies have elucidated the mechanisms underlying the formation and expression of drug-related cue memories. CRF in the brain plays a critical role in reward-driven associative learning. During the formation or consolidation process (CPP expression), the majority of the CRF-positive neurons in the PVN, central nucleus of amygdale (CeA), and bed nucleus of stria terminalis (BNST) coexpresses pCREB after morphine-induced CPP, suggesting that drug-paired context could trigger neuronal activity in the brain stress system [29]. Morphine-treated mice in their home cage do not show any changes in total CRF/CREB positive neurons, indicating

In organism and human models, drug reward can be assessed using a Pavlovian conditioning procedure known as conditioned place preference/conditioned place aversion (CPP/CPA) [5–7]. CPP for the drug-paired environment is predicted by self-reported measures of drug liking in humans [6]. CPA for the drug-paired environment is used to infer the dysphoric properties of drugs, including opioid receptor antagonists [8]. Many neurotransmitters, neurotrophic factors, and protein kinases have been delineated in the regulation of the formation and expression of drugassociated reward memories and withdrawal-associated aversive memories [9–13]. Corticotrophin-releasing factor (CRF) in the brain plays a critical role in reward- and aversion-driven associative learning. However, it is not clear whether it does this by a common mechanism or by separated mechanisms that can be dissociated. The knowledge of these mechanisms could lead to more effective treatments for addictive processes. CRF and its CRF1 receptor (CRF1R) are widely distributed and in a highly conserved way in several brain regions, including the hippocampal formation, involved in reward reinforcement, craving and aversive effects of drug of abuse [14–17]. At the extrahypothalamic level, CRF acts as a neuroregulator of the behavioral and emotional integration of environmental and endogenous stimuli associated with drug dependence [18, 19]. In the hippocampal dentate gyrus (DG), an important brain region involved in saving similar experiences and contexts [20], CRF is released from inhibitory interneurons [21] through CRF1R [14] by environmental signals. CRF1R activation stimulates Gαs protein, promoting the induction of the protein kinase A/cAMP response element binding protein (CREB) pathway [22]. CREB activity in the brain is critical for learning and memory processes [23], and it has been reported to be involved in the expression of opioid dependence. The activation of CREB, as one of the main downstream effectors of extracellular signal-regulated kinase (ERK), accelerates the transcription of CREB-dependent genes such as the brain-derived neurotrophic factor (BDNF). With respect to hypothalamus, CRF release from paraventricular nucleus (PVN) controls the hypothalamic-pituitary-adrenal (HPA) axis responses to stress and drug addiction [24–26]. CRF neurons in the PVN and CRF fibber in DG have direct connexion with dopaminergic neurons located in the ventral tegmental area (VTA) projecting to

**54**

### **Figure 1.**

*CREB activation in PVN (A) and DG (C) after morphine-induced CPP. Scale bar 100 μm. Quantitative analysis of pCREB immunodetection in PVN (B) and DG (D). Data are expressed as mean ± SEM. \*\*p < 0.01, \*\*\*p < 0.001 versus vehicle (veh) + saline (S); +p < 0.05, +++p < 0.001 versus veh + morphine (M). CP-154,526 (CP). Optical density (OD).*

(cAMP/PKA/CREB). However, CRF through CRFR1 is capable of activating other Gα types such as Gαs and activate inositol triphosphate (IP3) cascade. An enhancement in the concentration of secondary messengers (cAMP, IP3, and Ca2+) in cells, induced by CRF1R agonists, promotes the activation of several transcriptional factors such as CREB, AP-1, NF-κB, and the calcium response element (CARE) [47–53]. In this sense, the antagonist of the CRF1R, CP-154,526, by blocking the postsynaptic CRF1R, inhibited CREB phosphorylation in PVN and DG. Moreover, morphine treatment induced an increase in CRF fiber immunodetection in DG, suggesting an elevated CRF release, which was prevented by pretreatment with this antagonist. Since CRF1R activation increases Ca2+ levels, it is possible that CP-154,526 inhibits CRF release by blocking presynaptic CRF1R in PVN.

Several evidences suggest that CREB phosphorylation represents a site of convergence for various signaling pathways and alters gene expression [40]. CREB activation can also be regulated by the family of the redox protein Trx-1 [54]. In addition to its antioxidant activity, Trx-1 has been shown to play a crucial role in cellular signaling by controlling several important members of the signal transduction pathway. Thus, NF-κB, p38 mitogen-activated protein kinases, activator protein-1, CREB (as mentioned before), estrogen receptor, glucocorticoid receptor, and p53 are the targets of Trx-1 [55]. Data from our laboratory have shown that morphine-induced CPP increases Trx-1 expression in DG (**Figure 3**). Trx-1 might activate CREB

**57**

**Figure 2.**

*(M). CP-154,526 (CP). Optical density (OD).*

*Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression…*

phosphorylation, thus increasing the rewarding effects of morphine. In agreement with our results, other studies have also observed an increased Trx-1 expression following morphine or methamphetamine administration [56]. Upregulation of CREB activity induced by methamphetamine was suppressed by Trx-1siRNA, which suggests that Trx-1 is necessary for CREB activation [55, 56]. Moreover, morphineinduced Trx-1 expression is blocked by naloxone, indicating that morphine induces Trx-1 expression via activating opioid receptors [57]. Results from our laboratory showing a positive relationship between morphine rewarding effects, and Trx-1 expression are in contrast with another study [58] demonstrating that geranylgeranylacetone induces Trx-1 and, concomitantly, reduces morphine-induced CPP. These variations could be explained by the differential regulating roles of NAc and hippocampus. Besides, CREB expression has been shown to be increased in hippocampus but decreased in NAc after morphine conditioning [40], which suggests that CREB activity is differently regulated depending on the brain area studied. Our investigations have demonstrated a large number of pCREB/Trx-1 double-labeled neurons in DG (**Figure 3**). These neuron colocalizations in DG suggest that CREB might be activated by Trx-1 in this brain nucleus involved in memory consolidation processes.

*CRF/pCREB double-labeling photomicrographs in PVN (A). The upper right side of the figure shows the quantitative analysis of double-labeled neurons (B). CRF fiber photomicrographs in the DG (C). The down right side of the figure shows the CRF fiber density in the DG (D). Scale bar 100 or 50 μm. Data are expressed as mean ± SEM. \*\*\*p < 0.001 versus vehicle (veh) + saline (S); ++p < 0.01, +++p < 0.001 versus veh + morphine* 

*DOI: http://dx.doi.org/10.5772/intechopen.80504*

*Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression… DOI: http://dx.doi.org/10.5772/intechopen.80504*

### **Figure 2.**

*Opioids - From Analgesic Use to Addiction*

(cAMP/PKA/CREB). However, CRF through CRFR1 is capable of activating other Gα types such as Gαs and activate inositol triphosphate (IP3) cascade. An enhancement in the concentration of secondary messengers (cAMP, IP3, and Ca2+) in cells, induced by CRF1R agonists, promotes the activation of several transcriptional factors such as CREB, AP-1, NF-κB, and the calcium response element (CARE) [47–53]. In this sense, the antagonist of the CRF1R, CP-154,526, by blocking the postsynaptic CRF1R, inhibited CREB phosphorylation in PVN and DG. Moreover, morphine treatment induced an increase in CRF fiber immunodetection in DG, suggesting an elevated CRF release, which was prevented by pretreatment with this antagonist. Since CRF1R activation increases Ca2+ levels, it is possible that CP-154,526 inhibits CRF release by blocking presynaptic CRF1R in PVN.

*CREB activation in PVN (A) and DG (C) after morphine-induced CPP. Scale bar 100 μm. Quantitative analysis of pCREB immunodetection in PVN (B) and DG (D). Data are expressed as mean ± SEM. \*\*p < 0.01, \*\*\*p < 0.001 versus vehicle (veh) + saline (S); +p < 0.05, +++p < 0.001 versus veh + morphine (M). CP-154,526* 

Several evidences suggest that CREB phosphorylation represents a site of convergence for various signaling pathways and alters gene expression [40]. CREB activation can also be regulated by the family of the redox protein Trx-1 [54]. In addition to its antioxidant activity, Trx-1 has been shown to play a crucial role in cellular signaling by controlling several important members of the signal transduction pathway. Thus, NF-κB, p38 mitogen-activated protein kinases, activator protein-1, CREB (as mentioned before), estrogen receptor, glucocorticoid receptor, and p53 are the targets of Trx-1 [55]. Data from our laboratory have shown that morphine-induced CPP increases Trx-1 expression in DG (**Figure 3**). Trx-1 might activate CREB

**56**

**Figure 1.**

*(CP). Optical density (OD).*

*CRF/pCREB double-labeling photomicrographs in PVN (A). The upper right side of the figure shows the quantitative analysis of double-labeled neurons (B). CRF fiber photomicrographs in the DG (C). The down right side of the figure shows the CRF fiber density in the DG (D). Scale bar 100 or 50 μm. Data are expressed as mean ± SEM. \*\*\*p < 0.001 versus vehicle (veh) + saline (S); ++p < 0.01, +++p < 0.001 versus veh + morphine (M). CP-154,526 (CP). Optical density (OD).*

phosphorylation, thus increasing the rewarding effects of morphine. In agreement with our results, other studies have also observed an increased Trx-1 expression following morphine or methamphetamine administration [56]. Upregulation of CREB activity induced by methamphetamine was suppressed by Trx-1siRNA, which suggests that Trx-1 is necessary for CREB activation [55, 56]. Moreover, morphineinduced Trx-1 expression is blocked by naloxone, indicating that morphine induces Trx-1 expression via activating opioid receptors [57]. Results from our laboratory showing a positive relationship between morphine rewarding effects, and Trx-1 expression are in contrast with another study [58] demonstrating that geranylgeranylacetone induces Trx-1 and, concomitantly, reduces morphine-induced CPP. These variations could be explained by the differential regulating roles of NAc and hippocampus. Besides, CREB expression has been shown to be increased in hippocampus but decreased in NAc after morphine conditioning [40], which suggests that CREB activity is differently regulated depending on the brain area studied. Our investigations have demonstrated a large number of pCREB/Trx-1 double-labeled neurons in DG (**Figure 3**). These neuron colocalizations in DG suggest that CREB might be activated by Trx-1 in this brain nucleus involved in memory consolidation processes.

### **Figure 3.**

*Characterization of pCREB and Trx-1 immunostaining in the dentate gyrus (DG) after morphine-induced CPP. (A) Schematic illustration showing the analyzed region of the DG (diagram modified from Franklin & Paxinos) [59]. Coordinate −1.94 mm from Bregma. (B) High-magnification image of a mouse midbrain coronal section immunostained for pCREB and Trx-1. Scale bar 100 μm. Representative confocal images of pCREB (red) (C–F) and Trx-1 (green) (C*′*–F*′*). Colocalization (pCREB/Trx-1) is shown in C*″*–F*″ *by yellow-orange neurons in the merged images. Scale bar 20 μm. Graphs on the right indicate the mean total number of pCREB (G), Trx-1 (H), and double-labeled (pCREB/Trx-1) neurons (I). Data are expressed as mean ± SEM. \*\*\*p < 0.001 versus vehicle (veh) + saline (S); +p < 0.05, ++p < 0.01 versus veh + morphine (M). CP-154,526 (CP).*

Due to the important role of TRX-1 in regulating the cellular redox balance, the induction of TRX-1 expression following morphine CPP could be associated to a mechanism of neural protection against a stressful situation.

Pretreatment with CP-154,526 completely blocks morphine-induced CPP elevation of Trx-1 expression in DG (**Figure 3**).

We have also shown an increase in the number of pCREB neurons coexpressing Trx-1 following morphine-induced CPP, so CRF1R could be involved in CREB phosphorylation, probably through a Trx-1-dependent way. The exact mechanism by which the CRF system participates in Trx-1 signaling regulation in DG is not completely understood. One possible explanation could indicate that pCREB binds to CRE in the 5′-upstream sequence of Trx-1 gene, thus inducing Trx-1 expression to regulate its phosphorylation. In agreement with this hypothesis, other authors have demonstrated that ephedrine promotes Trx-1 expression via the β-adrenergic

**59**

**Figure 4.**

*(M). CP-154,526 (CP).*

*Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression…*

receptor/cyclic AMP/PKA/DARPP-32 signaling pathway [60]. Besides, methamphetamine-induced CREB activity in rat pheochromocytoma cells was shown to be

On the other hand, BDNF, an important neurotrophin for synaptic plasticity, is one of the molecular candidates underlying the development of persistent

*Characterization of pCREB and Trx-1 immunostaining in the paraventricular nucleus (PVN) after morphine-induced CPP. (A) Schematic illustration showing the analyzed region of the PVN (diagram modified from Franklin & Paxinos) [59]. Coordinate −0.82 mm from Bregma. (B) High-magnification image of a mouse midbrain coronal section immunostained for pCREB and Trx-1. Scale bar 100 μm. Representative confocal images of pCREB (red) (C–F) and Trx-1 (green) (C*′*–F*′*). Colocalization (pCREB/Trx-1) is shown in C*″*–F*″ *by yellow-orange neurons in the merged images. Scale bar 20 μm. Graphs on the right indicate the mean total number of pCREB (G), Trx-1 (H), and double-labeled (pCREB/Trx-1) neurons (I). Data are expressed as mean ± SEM. \*\*p < 0.01, versus vehicle (veh) + saline (S); ++p < 0.01, versus veh + morphine* 

As shown in **Figure 4**, morphine-induced CPP increases the number of pCREBpositive neurons in PVN, an increase that was blocked by CP-154,526 treatment. However, there are no changes in the number of Trx-1 positive neurons or in the

*DOI: http://dx.doi.org/10.5772/intechopen.80504*

double labeled neurons (pCREB/Trx-1).

regulated by Trx-1 [56].

*Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression… DOI: http://dx.doi.org/10.5772/intechopen.80504*

receptor/cyclic AMP/PKA/DARPP-32 signaling pathway [60]. Besides, methamphetamine-induced CREB activity in rat pheochromocytoma cells was shown to be regulated by Trx-1 [56].

As shown in **Figure 4**, morphine-induced CPP increases the number of pCREBpositive neurons in PVN, an increase that was blocked by CP-154,526 treatment. However, there are no changes in the number of Trx-1 positive neurons or in the double labeled neurons (pCREB/Trx-1).

On the other hand, BDNF, an important neurotrophin for synaptic plasticity, is one of the molecular candidates underlying the development of persistent

### **Figure 4.**

*Opioids - From Analgesic Use to Addiction*

Due to the important role of TRX-1 in regulating the cellular redox balance, the induction of TRX-1 expression following morphine CPP could be associated to a

*Characterization of pCREB and Trx-1 immunostaining in the dentate gyrus (DG) after morphine-induced CPP. (A) Schematic illustration showing the analyzed region of the DG (diagram modified from Franklin & Paxinos) [59]. Coordinate −1.94 mm from Bregma. (B) High-magnification image of a mouse midbrain coronal section immunostained for pCREB and Trx-1. Scale bar 100 μm. Representative confocal images of pCREB (red) (C–F) and Trx-1 (green) (C*′*–F*′*). Colocalization (pCREB/Trx-1) is shown in C*″*–F*″ *by yellow-orange neurons in the merged images. Scale bar 20 μm. Graphs on the right indicate the mean total number of pCREB (G), Trx-1 (H), and double-labeled (pCREB/Trx-1) neurons (I). Data are expressed as mean ± SEM. \*\*\*p < 0.001 versus vehicle (veh) + saline (S); +p < 0.05, ++p < 0.01 versus veh + morphine (M). CP-154,526 (CP).*

Pretreatment with CP-154,526 completely blocks morphine-induced CPP eleva-

We have also shown an increase in the number of pCREB neurons coexpressing Trx-1 following morphine-induced CPP, so CRF1R could be involved in CREB phosphorylation, probably through a Trx-1-dependent way. The exact mechanism by which the CRF system participates in Trx-1 signaling regulation in DG is not completely understood. One possible explanation could indicate that pCREB binds to CRE in the 5′-upstream sequence of Trx-1 gene, thus inducing Trx-1 expression to regulate its phosphorylation. In agreement with this hypothesis, other authors have demonstrated that ephedrine promotes Trx-1 expression via the β-adrenergic

mechanism of neural protection against a stressful situation.

tion of Trx-1 expression in DG (**Figure 3**).

**58**

**Figure 3.**

*Characterization of pCREB and Trx-1 immunostaining in the paraventricular nucleus (PVN) after morphine-induced CPP. (A) Schematic illustration showing the analyzed region of the PVN (diagram modified from Franklin & Paxinos) [59]. Coordinate −0.82 mm from Bregma. (B) High-magnification image of a mouse midbrain coronal section immunostained for pCREB and Trx-1. Scale bar 100 μm. Representative confocal images of pCREB (red) (C–F) and Trx-1 (green) (C*′*–F*′*). Colocalization (pCREB/Trx-1) is shown in C*″*–F*″ *by yellow-orange neurons in the merged images. Scale bar 20 μm. Graphs on the right indicate the mean total number of pCREB (G), Trx-1 (H), and double-labeled (pCREB/Trx-1) neurons (I). Data are expressed as mean ± SEM. \*\*p < 0.01, versus vehicle (veh) + saline (S); ++p < 0.01, versus veh + morphine (M). CP-154,526 (CP).*

### **Figure 5.**

*Western-blotting analysis of BDNF in the dentate gyrus (DG) and paraventricular nucleus (PVN) from animals pretreated with vehicle (veh) or CP-154,526 (CP) before saline or morphine. The immunoreactivity corresponding to BDNF is expressed as a percentage of that in the control group defined as 100% value. \*\*\*p < 0.001 versus morphine + CP; +p < 0.05 versus saline + veh.*

neuroplastic adaptation that regulates drug addiction [61]. Several lines of evidence indicate that chronic morphine treatment triggers ERK activation in different brain regions [62]. ERK phosphorylates CREB and active (phosphorylated) CREB stimulates the expression of target genes, including BDNF [63–65]. Chronic morphine use has been shown to increase the expression of BDNF in the NAc and hippocampus [61, 66, 67]. According to these data, our findings demonstrated that morphine-induced CPP activates BDNF signaling in the DG without any changes in the saline group (**Figure 5**), demonstrating that repeated morphine with context exposure, but not merely the context, increases BDNF expression in DG, suggesting that BDNF is implicated in drug-induced contextual memory formation. Therefore, BDNF is a crucial signal molecule involved in morphine dependence. However, whether this molecule is regulated in a CRF1R-dependent manner remains largely unknown: CP-154,526 attenuated CREB-BDNF expression (**Figures 4** and **5**) and prevented morphine-induced CPP [29]. Taken together, CRF1R-mediated CREB-BDNF signaling changes may regulate morphine reward through modulating contextual memory in the hippocampus.

### **3. Role of CRF1 receptor in the aversive effects induced by naloxone-precipitated withdrawal**

The physical component of morphine withdrawal syndrome can be assessed by scoring some somatic withdrawal signs after morphine exposure [68]. Recent results from our group have demonstrated significant alterations in some morphine withdrawal signs such as body weight loss, rearing, rubbing, grooming, diarrhea, freezing, and time to first immobility in wild type morphine-withdrawn animals compared with controls treated with saline (**Figure 6**). Besides, and in agreement with previous studies [69–71], our laboratory has shown that body weight loss (**Figure 6H**), freezing (**Figure 6F**), and diarrhea (**Figure 6E**) are significantly attenuated in CRF1R KO mice although an increase in jumping in CRF1R KO mice was observed (**Figure 6A**), as it has been described previously by other authors [72]. Jumping is a sensitive and commonly used index of naloxone-induced withdrawal [73–76]. However, it is

**61**

**Figure 6.**

*treated with morphine + nx.*

*Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression…*

important to clarify that different neural elements mediate several withdrawal behaviors [77, 78]. Thus, it is not easy to extrapolate naloxone-precipitated jumping in

*Behavior effects by naloxone (nx)-precipitated morphine withdrawal in wild type (WT) or knockout (CRF1R KO) mice. The following somatic signs, (A) jumping, (B) rearing, (C) rubbing, (D) grooming, (E) diarrhea, (F) freezing behavior, and (H) body weight loss, induced after nx (1 mg/kg, s.c.)-injection to morphine or saline-treated mice during 18 min, were evaluated. The time to first immobilization (G) was also evaluated. Data are expressed as the mean ± SEM. \$\$p < 0.01 versus WT mice treated with morphine + nx; \*\*p < 0.01 versus WT mice treated with saline + nx; +p < 0.05, ++p < 0.01, +++p < 0.001 versus WT mice treated with saline+nx; ##p < 0.01, ###p < 0.001 versus KO mice treated with saline + nx; &&&p < 0.001 versus WT mice* 

It is commonly accepted that affective drug withdrawal symptoms are of major motivational significance in contributing to relapse and continued drug use; thus, it is important to understand the mechanisms that mediate affective behaviors during morphine withdrawal. CPA paradigm is a highly sensitive animal model for the measurement of the negative affective component of drug withdrawal as well as to investigate the neural substrates underlying the aversive memory associated with drug withdrawal [79, 80]. In this model, a morphine-dependent animal undergoing

CRF1R KO mice to other physical symptoms like body weight loss.

**4. Role of CRF1 receptor in CPA expression and extinction**

*DOI: http://dx.doi.org/10.5772/intechopen.80504*

*Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression… DOI: http://dx.doi.org/10.5772/intechopen.80504*

### **Figure 6.**

*Opioids - From Analgesic Use to Addiction*

contextual memory in the hippocampus.

*\*\*\*p < 0.001 versus morphine + CP; +p < 0.05 versus saline + veh.*

**naloxone-precipitated withdrawal**

**3. Role of CRF1 receptor in the aversive effects induced by** 

The physical component of morphine withdrawal syndrome can be assessed by scoring some somatic withdrawal signs after morphine exposure [68]. Recent results from our group have demonstrated significant alterations in some morphine withdrawal signs such as body weight loss, rearing, rubbing, grooming, diarrhea, freezing, and time to first immobility in wild type morphine-withdrawn animals compared with controls treated with saline (**Figure 6**). Besides, and in agreement with previous studies [69–71], our laboratory has shown that body weight loss (**Figure 6H**), freezing (**Figure 6F**), and diarrhea (**Figure 6E**) are significantly attenuated in CRF1R KO mice although an increase in jumping in CRF1R KO mice was observed (**Figure 6A**), as it has been described previously by other authors [72]. Jumping is a sensitive and commonly used index of naloxone-induced withdrawal [73–76]. However, it is

neuroplastic adaptation that regulates drug addiction [61]. Several lines of evidence indicate that chronic morphine treatment triggers ERK activation in different brain regions [62]. ERK phosphorylates CREB and active (phosphorylated) CREB stimulates the expression of target genes, including BDNF [63–65]. Chronic morphine use has been shown to increase the expression of BDNF in the NAc and hippocampus [61, 66, 67]. According to these data, our findings demonstrated that morphine-induced CPP activates BDNF signaling in the DG without any changes in the saline group (**Figure 5**), demonstrating that repeated morphine with context exposure, but not merely the context, increases BDNF expression in DG, suggesting that BDNF is implicated in drug-induced contextual memory formation. Therefore, BDNF is a crucial signal molecule involved in morphine dependence. However, whether this molecule is regulated in a CRF1R-dependent manner remains largely unknown: CP-154,526 attenuated CREB-BDNF expression (**Figures 4** and **5**) and prevented morphine-induced CPP [29]. Taken together, CRF1R-mediated CREB-BDNF signaling changes may regulate morphine reward through modulating

*Western-blotting analysis of BDNF in the dentate gyrus (DG) and paraventricular nucleus (PVN) from animals pretreated with vehicle (veh) or CP-154,526 (CP) before saline or morphine. The immunoreactivity corresponding to BDNF is expressed as a percentage of that in the control group defined as 100% value.* 

**60**

**Figure 5.**

*Behavior effects by naloxone (nx)-precipitated morphine withdrawal in wild type (WT) or knockout (CRF1R KO) mice. The following somatic signs, (A) jumping, (B) rearing, (C) rubbing, (D) grooming, (E) diarrhea, (F) freezing behavior, and (H) body weight loss, induced after nx (1 mg/kg, s.c.)-injection to morphine or saline-treated mice during 18 min, were evaluated. The time to first immobilization (G) was also evaluated. Data are expressed as the mean ± SEM. \$\$p < 0.01 versus WT mice treated with morphine + nx; \*\*p < 0.01 versus WT mice treated with saline + nx; +p < 0.05, ++p < 0.01, +++p < 0.001 versus WT mice treated with saline+nx; ##p < 0.01, ###p < 0.001 versus KO mice treated with saline + nx; &&&p < 0.001 versus WT mice treated with morphine + nx.*

important to clarify that different neural elements mediate several withdrawal behaviors [77, 78]. Thus, it is not easy to extrapolate naloxone-precipitated jumping in CRF1R KO mice to other physical symptoms like body weight loss.

### **4. Role of CRF1 receptor in CPA expression and extinction**

It is commonly accepted that affective drug withdrawal symptoms are of major motivational significance in contributing to relapse and continued drug use; thus, it is important to understand the mechanisms that mediate affective behaviors during morphine withdrawal. CPA paradigm is a highly sensitive animal model for the measurement of the negative affective component of drug withdrawal as well as to investigate the neural substrates underlying the aversive memory associated with drug withdrawal [79, 80]. In this model, a morphine-dependent animal undergoing

withdrawal is exposed to a particular environment for a period of time. When later is given the opportunity to freely explore the apparatus, animals trained in this way tend to avoid the previously paired context due to the association between the context and aversive memories of drug withdrawal [79].

The extinction of this aversion occurs if the association is weakened by repeated exposure to the withdrawal-associated context in the absence of the conditioned stimulus, and the initial response (CPA) can be reinstated by a drug priming injection, stress or by conditioned cues. Extinction is complete when animals no longer avoid the previously cue-paired compartment. Typically, while memory reconsolidation requires single context reexposure, extinction requires multiple cue reexposures [81]. For example, fear conditioning studies suggest that the extinction process does not eliminate the initial context, but the organism learns that this cue does not cause the previous stimulus [82]. Thus, extinction requires associative learning, consolidation, and the formation of a new memory [83].

Recently, our group has investigated the mechanism underlying CPA expression and extinction. These experiments showed that morphine administration induced a significant place aversion for the naloxone-paired compartment, compared to the saline group. However, CRF1R KO mice presented less aversion than wild type mice (**Figure 7A**).

### **Figure 7.**

*(A) CPA expression induced by naloxone (nx, 1 mg/kg, s.c.) in wild type (WT) or knockout (CRF1R KO) mice treated with morphine or saline. The score was calculated for each mouse as the difference between the postconditioning and the preconditioning time spent in the naloxone-paired compartment. (B) Extinction of CPA training. Aversion scores from day 5 to 13 for WT and CRF1R KO mice are shown. Data are expressed as the mean ± SEM. +++p < 0.001 versus WT mice treated with saline + nx, &p < 0.05, &&p < 0.01, &&&p < 0.001 versus WT mice treated with morphine + nx.*

**63**

**Figure 8.**

*Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression…*

There is much information about the neurobiological mechanisms involving extinction of reward memory of drug taking [84–86]. However, little information is known about extinction of aversive memory of drug withdrawal [87]. Previous studies have demonstrated that the aversive effects of opiates might be related to basal genotype differences in the brain systems [88]. Accordingly, we have clearly demonstrated that the genetic disruption of the CRF/CRF1R pathway decreases the

Thus, results obtained by our laboratory regarding CPA expression and extinc-

**5. Role of HHA axis in the CPA induced by morphine withdrawal**

It is well established that acute withdrawal of all major drugs of abuse dysregulates the HPA axis and alters CRF activity in the PVN of the hypothalamus, with a common response of increased adrenocorticotropic hormone (ACTH) and corticosterone [89], which mediate somatic and aversive components of withdrawal [72, 90–92]. To evaluate whether a causal link exists between CRF1R activation and HPA axis, our group has measured plasma ACTH and corticosterone levels in wild type and CRF1R KO mice after naloxone-induced CPA expression and CPA extinction (**Figure 8**). Our investigations have shown that plasma ACTH levels are increased in wild type mice although plasma corticosterone levels are not changed following CPA expression. These results indicate that ACTH-independent mechanisms could have an important role in the regulation of the adrenal stress system to appropriately adapt its response to physiological necessities, and even the presence of pituitary ACTH is basic for adrenocortical function. Numerous lines of evidence indicate that a large number of neuropeptides, neurotransmitters, growth

*Effect of CPA expression and CPA extinction training on ACTH (A and B) and corticosterone (C and D) plasma levels in wild type (WT) and knockout (CRF1R KO) mice. Data are expressed as the mean ± SEM. +++p < 0.001* 

*versus WT mice treated with saline + nx, &&&p < 0.001 versus WT mice treated with morphine + nx.*

tion suggest an important role for CRF1R in aversive memory.

*DOI: http://dx.doi.org/10.5772/intechopen.80504*

period of CPA extinction (**Figure 7B**).

*Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression… DOI: http://dx.doi.org/10.5772/intechopen.80504*

There is much information about the neurobiological mechanisms involving extinction of reward memory of drug taking [84–86]. However, little information is known about extinction of aversive memory of drug withdrawal [87]. Previous studies have demonstrated that the aversive effects of opiates might be related to basal genotype differences in the brain systems [88]. Accordingly, we have clearly demonstrated that the genetic disruption of the CRF/CRF1R pathway decreases the period of CPA extinction (**Figure 7B**).

Thus, results obtained by our laboratory regarding CPA expression and extinction suggest an important role for CRF1R in aversive memory.

### **5. Role of HHA axis in the CPA induced by morphine withdrawal**

It is well established that acute withdrawal of all major drugs of abuse dysregulates the HPA axis and alters CRF activity in the PVN of the hypothalamus, with a common response of increased adrenocorticotropic hormone (ACTH) and corticosterone [89], which mediate somatic and aversive components of withdrawal [72, 90–92]. To evaluate whether a causal link exists between CRF1R activation and HPA axis, our group has measured plasma ACTH and corticosterone levels in wild type and CRF1R KO mice after naloxone-induced CPA expression and CPA extinction (**Figure 8**). Our investigations have shown that plasma ACTH levels are increased in wild type mice although plasma corticosterone levels are not changed following CPA expression. These results indicate that ACTH-independent mechanisms could have an important role in the regulation of the adrenal stress system to appropriately adapt its response to physiological necessities, and even the presence of pituitary ACTH is basic for adrenocortical function. Numerous lines of evidence indicate that a large number of neuropeptides, neurotransmitters, growth

**Figure 8.**

*Effect of CPA expression and CPA extinction training on ACTH (A and B) and corticosterone (C and D) plasma levels in wild type (WT) and knockout (CRF1R KO) mice. Data are expressed as the mean ± SEM. +++p < 0.001 versus WT mice treated with saline + nx, &&&p < 0.001 versus WT mice treated with morphine + nx.*

*Opioids - From Analgesic Use to Addiction*

(**Figure 7A**).

context and aversive memories of drug withdrawal [79].

learning, consolidation, and the formation of a new memory [83].

withdrawal is exposed to a particular environment for a period of time. When later is given the opportunity to freely explore the apparatus, animals trained in this way tend to avoid the previously paired context due to the association between the

The extinction of this aversion occurs if the association is weakened by repeated exposure to the withdrawal-associated context in the absence of the conditioned stimulus, and the initial response (CPA) can be reinstated by a drug priming injection, stress or by conditioned cues. Extinction is complete when animals no longer avoid the previously cue-paired compartment. Typically, while memory reconsolidation requires single context reexposure, extinction requires multiple cue reexposures [81]. For example, fear conditioning studies suggest that the extinction process does not eliminate the initial context, but the organism learns that this cue does not cause the previous stimulus [82]. Thus, extinction requires associative

Recently, our group has investigated the mechanism underlying CPA expression and extinction. These experiments showed that morphine administration induced a significant place aversion for the naloxone-paired compartment, compared to the saline group. However, CRF1R KO mice presented less aversion than wild type mice

*(A) CPA expression induced by naloxone (nx, 1 mg/kg, s.c.) in wild type (WT) or knockout (CRF1R KO) mice treated with morphine or saline. The score was calculated for each mouse as the difference between the postconditioning and the preconditioning time spent in the naloxone-paired compartment. (B) Extinction of CPA training. Aversion scores from day 5 to 13 for WT and CRF1R KO mice are shown. Data are expressed as the mean ± SEM. +++p < 0.001 versus WT mice treated with saline + nx, &p < 0.05, &&p < 0.01,* 

*&&&p < 0.001 versus WT mice treated with morphine + nx.*

**62**

**Figure 7.**

factors, and bacterial ligands can influence the release of adrenal glucocorticoids independently of pituitary ACTH [93]. Adrenocortical cells express a large diversity of receptors for these factors, thus triggering potential direct actions on glucocorticoids release. Damage in the upstream stress regulating pathways in the brain leads to a rupture between ACTH and corticosterone, which suggests that central nervous system neurocircuits can regulate HPA axis response at both pituitary and adrenal sites [94]. Our results also indicate that CPA expression-induced ACTH release is attenuated in CRF1R KO mice. In agreement with these observations, it has been reported fewer ACTH levels in morphine withdrawn animals treated with CRF1R antagonists [70]. Besides, a role for the HPA axis and extra-hypothalamic brain circuitry in somatic, molecular, and endocrine changes induced during opioid withdrawal has been described [72]. ACTH plasma levels returned to basal in wild type and CRF1R KO mice after CPA extinction. These results suggest that CPA expression is, at least, partially due to an increase in plasma ACTH levels which can be decreased after naloxone CPA extinction.

### **6. Conclusion**

CP-154,526 administration or genetic deletion of CRF1R impairs CPP and CPA learning, suggesting that the expression of reward and aversive learning and memory shares some common neural circuits related with CRF/CRF1R signaling. During the formation or consolidation process (CPP expression), the majority of phospho-CREB positive neurons in DG coexpresses Trx-1, in parallel with an increased expression of BDNF, suggesting that Trx-1 could activate CREB and this in turn accelerates the transcription of CREB-dependent genes such as BDNF. However, CP-154,526 diminishes CPP expression, in parallel with a block of phospho-CREB/Trx-1 colocalization and BDNF expression, suggesting that Trx-1- CREB-BDNF signaling could be essential for memory formation or consolidation. In addition, CPA expression training increases plasma ACTH levels, which is critical for the maintenance of aversive memories associated with drug withdrawal. Genetic deletion of CRF1R (KO mice) induces a reduction in CPA expression accompanied with a higher decrease in ACTH plasma levels. CPA extinction period is reduced in KO mice, indicating a role for CRF1R in the aversive memory retrieval. Altogether, these results indicate a critical role for CRF, through CRF1R, in molecular changes involved in reward memory-associated behaviors and in aversive memory expression and extinction. The disruption of these processes by CRF1 antagonists might lead to effective treatments in drug addiction.

### **Acknowledgements**

This research was supported by a grant from the Ministerio de Economía, Industria y Competitividad (SAF2017-85679-R).

**65**

**Author details**

Murcia, Spain

and María L. Laorden

provided the original work is properly cited.

\*Address all correspondence to: palmela@um.es

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Pilar Almela\*, Juan A. García-Carmona, Elena Martínez-Laorden, María V. Milanés

Department of Pharmacology, Faculty of Medicine, University of Murcia,

*Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression…*

*DOI: http://dx.doi.org/10.5772/intechopen.80504*

*Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression… DOI: http://dx.doi.org/10.5772/intechopen.80504*

### **Author details**

*Opioids - From Analgesic Use to Addiction*

be decreased after naloxone CPA extinction.

lead to effective treatments in drug addiction.

Industria y Competitividad (SAF2017-85679-R).

**Acknowledgements**

**6. Conclusion**

factors, and bacterial ligands can influence the release of adrenal glucocorticoids independently of pituitary ACTH [93]. Adrenocortical cells express a large diversity of receptors for these factors, thus triggering potential direct actions on glucocorticoids release. Damage in the upstream stress regulating pathways in the brain leads to a rupture between ACTH and corticosterone, which suggests that central nervous system neurocircuits can regulate HPA axis response at both pituitary and adrenal sites [94]. Our results also indicate that CPA expression-induced ACTH release is attenuated in CRF1R KO mice. In agreement with these observations, it has been reported fewer ACTH levels in morphine withdrawn animals treated with CRF1R antagonists [70]. Besides, a role for the HPA axis and extra-hypothalamic brain circuitry in somatic, molecular, and endocrine changes induced during opioid withdrawal has been described [72]. ACTH plasma levels returned to basal in wild type and CRF1R KO mice after CPA extinction. These results suggest that CPA expression is, at least, partially due to an increase in plasma ACTH levels which can

CP-154,526 administration or genetic deletion of CRF1R impairs CPP and CPA learning, suggesting that the expression of reward and aversive learning and memory shares some common neural circuits related with CRF/CRF1R signaling. During the formation or consolidation process (CPP expression), the majority of phospho-CREB positive neurons in DG coexpresses Trx-1, in parallel with an increased expression of BDNF, suggesting that Trx-1 could activate CREB and this in turn accelerates the transcription of CREB-dependent genes such as BDNF. However, CP-154,526 diminishes CPP expression, in parallel with a block of phospho-CREB/Trx-1 colocalization and BDNF expression, suggesting that Trx-1- CREB-BDNF signaling could be essential for memory formation or consolidation. In addition, CPA expression training increases plasma ACTH levels, which is critical for the maintenance of aversive memories associated with drug withdrawal. Genetic deletion of CRF1R (KO mice) induces a reduction in CPA expression accompanied with a higher decrease in ACTH plasma levels. CPA extinction period is reduced in KO mice, indicating a role for CRF1R in the aversive memory retrieval. Altogether, these results indicate a critical role for CRF, through CRF1R, in molecular changes involved in reward memory-associated behaviors and in aversive memory expression and extinction. The disruption of these processes by CRF1 antagonists might

This research was supported by a grant from the Ministerio de Economía,

**64**

Pilar Almela\*, Juan A. García-Carmona, Elena Martínez-Laorden, María V. Milanés and María L. Laorden Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain

\*Address all correspondence to: palmela@um.es

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[18] García-Carmona JA, Almela P, Baroja-Mazo A, Milanés MV, Laorden ML. Restricted role of CRF1R for the activity of brainstem catecholaminergic neurons in the negative state of morphine withdrawal. Psychopharmacology. 2012;**220**:379-393. DOI: 10.1007/s00213-011-2478-y

[19] Haass-Koffler CL, Bartlett SE. Stress and addiction: Contribution of the corticotropin releasing factor (CRF) system in neuroplasticity. Frontiers in Molecular Neuroscience. 2012;**5**:1-13. DOI: 10.3389/fnmol.2012.00091

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[22] Kasagi Y, Horiba N, Sakai K, Fukuda Y, Suda T. Involvement of cAMP-response element binding protein in corticotropin-releasing factor (CRF)-induced down-regulation of CRF receptor 1 gene expression in rat anterior pituitary cells. Journal of Neuroendocrinology. 2002;**14**:587-592

[23] Briand LA, Lee BG, Lelay J, Kaestner KH, Blendy JA. Serine 133 phosphorylation is not required for hippocampal CREB-mediated transcription and behavior. Learning & Memory. 2015;**22**:109-115. DOI: 10.1101/ lm.037044.114

[24] Dallman MF, Akana SF, Strack AM, Hanson ES, Sebastian RJ. The neural network that regulates energy balance is responsive to glucocorticoids and insulin and also regulates HPA axis responsivity at a site proximal to CRF neurons. Annals of the New York Academy of Sciences. 1995;**771**:730-742

[25] Martín F, Laorden ML, Milanés MV. Morphine withdrawal regulates phosphorylation of cAMP response element binding protein (CREB) through PKC in the nucleus tractus solitarius-A2 catecholaminergic neurons. Journal of Neurochemistry. 2009;**110**:1422-1432. DOI: 10.1111/j.1471-4159.2009.06234

[26] Martín F, Mora L, Laorden ML, Milanés MV. Protein kinase C phosphorylates the cAMP response element binding protein in the hypothalamic paraventricular nucleus during morphine withdrawal. British Journal of Pharmacology. 2011;**163**:857-875. DOI: 10.1111/j.1476-5381.2011.01287.x

[27] Voorn P, Jorritsma-Byham B, Van Dijk C, Buijs RM. The dopaminergic innervation of the ventral striatum in the rat: A light- and electronmicroscopical study with antibodies against dopamine. The Journal of Comparative Neurology. 1986;**251**: 84-99. DOI: 10.1002/cne.902510106

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**66**

*Opioids - From Analgesic Use to Addiction*

[1] Leshner AI. Drug abuse and addiction treatment research. The next generation. Archives of General

[2] O'Brien CP, Childress AR, McLellan AT, Ehrman R. Classical conditioning in drug-dependent humans. Annals of the New York Academy of Sciences.

accumbens core is necessary for heroin seeking. The Journal of Neuroscience. 2008;**28**:3170-3177. DOI: 10.1523/

[10] Lee AM, Messing RO. Protein kinases and addiction. Annals of the New York Academy of Sciences. 2008;**1141**:22-57. DOI: 10.1196/

[11] Ron D, Jurd R. The 'ups and downs' of signaling cascades in addiction. Science's STKE. 2005;**2005**:re14. DOI:

JNEUROSCI.5129-07

annals.1441.022

10.1126/stke.3092005re14

neuropharm.2008.06.059

10.1073/pnas.0403975101

[12] Russo SJ, Mazei-Robison MS, Ables JL, Nestler EJ. Neurotrophic factors and structural plasticity in addiction. Neuropharmacology. 2009;**56**(Suppl 1):73-82. DOI: 10.1016/j.

[13] Wise RA. Dopamine and reward: The anhedonia hypothesis 30 years on. Neurotoxicity Research. 2008;**14**: 169-183. DOI: 10.1007/BF03033808

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[74] El-Kadi AO, Sharif SI. The influence of various experimental conditions on the expression of naloxone-induced withdrawal symptoms in mice. General Pharmacology. 1994;**25**:1505-1510

[75] Miyamoto Y, Takemori AE. Relative involvement of supraspinal and spinal mu opioid receptors in morphine dependence in mice. Life Sciences. 1993;**52**:1039-1044

[76] Way EL, Lou HH, Shen FH. Simultaneous quantitative assessment of morphine tolerance and physical dependence. The Journal of Pharmacology and Experimental Therapeutics. 1969;**167**:1-8

[77] Brandao ML. Involvement of opioid mechanisms in the dorsal periaqueductal gray in drug abuse. Reviews in the Neurosciences. 1993;**4**:397-405

[78] Koob GF, Maldonado R, Stinus L. Neural substrates of opiate withdrawal. Trends in Neurosciences. 1992;**15**:186-191 [79] Myers KM, Bechtholt-Gompf AJ, Coleman BR, Carlezon WA. Extinction of conditioned opiate withdrawal in rats in a two-chambered place conditioning apparatus. Nature Protocols. 2012;**7**: 517-526. DOI: 10.1038/nprot.2011.458

[80] Stinus L, Caille S, Koob GF. Opiate withdrawal-induced place aversion lasts for up to 16 weeks. Psychopharmacology. 2000;**149**:115-120

[81] Power AE, Berlau DJ, McGaugh JL, Steward O. Anisomycin infused into the hippocampus fails to block "reconsolidation" but impairs extinction: The role of re-exposure duration. Learning & Memory. 2006;**13**:27-34. DOI: 10.1101/lm.91206

[82] Bouton ME. Context and behavioral processes in extinction. Learning & Memory. 2004;**11**:485-494. DOI: 10.1101/lm.78804

[83] Milad MR, Quirk GJ. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature. 2002;**420**:70-74. DOI: 10.1038/ nature01138

[84] Feltenstein MW, See RE. NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse. Neurobiology of Learning and Memory. 2007;**88**: 435-444. DOI: 10.1016/j. nlm.2007.05.006

[85] Hsu E, Packard MG. Medial prefrontal cortex infusions of bupivacaine or AP-5 block extinction of amphetamine conditioned place preference. Neurobiology of Learning and Memory. 2008;**89**:504-512. DOI: 10.1016/j.nlm.2007.08.006

[86] Torregrossa MM, Sanchez H, Taylor JR. D-cycloserine reduces the context specificity of pavlovian extinction of

cocaine cues through actions in the nucleus accumbens. The Journal of Neuroscience. 2010;**30**:10526-10533. DOI: 10.1523/JNEUROSCI.2523-10.2010

[87] Myers KM, Carlezon WA Jr. D-cycloserine facilitates extinction of naloxone-induced conditioned place aversion in morphine-dependent rats. Biological Psychiatry. 2010;**67**:85-87. DOI: 10.1016/j.biopsych.2009.08.015

[88] Solecki W, Turek A, Kubik J, Przewlocki R. Motivational effects of opiates in conditioned place preference and aversion paradigm-a study in three inbred strains of mice. Psychopharmacology. 2009;**207**:245-255. DOI: 10.1007/s00213-009-1672-7

[89] Ueno K, Maeda T, Kiguchi N, Kobayashi Y, Ozaki M, Kishioka S. Availability of serum corticosterone level for quantitative evaluation of morphine withdrawal in mice. Drug Discoveries & Therapeutics. 2011;**5**:71-75. DOI: 10.5582/ddt.2011.v5.2.71

[90] Contarino A, Papaleo F. The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal. Proceedings of the National Academy of Sciences of the United States of America. 2005;**102**:18649-18654. DOI: 10.1073/ pnas.0506999102

[91] Harris GC, Aston-Jones G. Activation in extended amygdale corresponds to alter hedonic processing during protracted morphine withdrawal. Behavioural Brain Research. 2007;**176**:251-258. DOI: 10.1016/j.bbr.2006.10.012

[92] Koob GF. A role for brain stress system in addiction. Neuron. 2008;**59**:11-34. DOI: 10.1016/j. neuron.2008.06.012

[93] Bornstein SR, Engeland WC, Ehrhart-Bornstein ME, Herman JP. Dissociation of ACTH and glucocorticoids. Trends in Endocrinology and Metabolism. 2008;**19**:175-180. DOI: 10.1016/j. tem.2008.01.009

[94] Choi DC, Furai AR, Evanson NK, Ostrander MM, Ulrich-Lai YM, Herman JP. Bed nucleus of the stria terminalis subregions differentially regulates hypothalamic-pituitary-adrenal axis activity: Implications for the integration of limbic inputs. The Journal of Neuroscience. 2007;**27**:2025-2034. DOI: 10.1523/JNEUROSCI.4301-06.2007

**73**

**Chapter 6**

**Abstract**

considerably.

**1. Introduction**

from an opioid overdose every day [6].

illicit drug in the USA [8].

Present and Future

Opioid Addiction

*and Marta Rodríguez-Arias*

Pharmacological Treatments for

*Maria Carmen Blanco-Gandía, Sandra Montagud-Romero* 

When treating opioid addiction, multidisciplinary treatment is highly recommended, but pharmacotherapy plays a key role. Although the ideal goal is to achieve complete abstinence, an elevated percentage of opioid addicts requires maintenance substitution therapy. In the first section of this chapter, we will focus on the current pharmacological interventions to treat opioid addiction, such as methadone, buprenorphine, and naltrexone. Thanks to these medications, people are able to go back to their normal lives, by preventing withdrawal symptoms, reducing craving, and increasing their adherence to psychotherapy. In the second section, based on the evidence that addiction induces neuroadaptive changes in several neurotransmission systems, we focus on the wide range of possible pharmacological developments at the preclinical and clinical levels, which in recent years have increased

Addiction is a chronic and multifactorial disorder characterized by compulsive drug seeking and use, despite its harmful consequences. Chronic opioid use induces profound molecular and behavioral changes, inducing long-lasting changes in brain plasticity [1]. During the use of the drug, reward and motivation circuits are modified, and new learning and memories are created in relation to the pleasurable effects of the drug and the context in which it is consumed [2]. These memories will later be responsible for the vulnerability to relapse even after a long period of withdrawal. In order to restructure these memories and avoid relapse and craving to opioids, the first recommended approach currently consists in combining psychotherapy with pharmacological substitution therapy [3]. Opioid addiction is currently a major medical and social problem, and its abuse and recreational use have been declared an epidemic in the USA [4, 5], with more than 90 people dying

Opioids are highly addictive because they induce euphoria (positive reinforcement) and the cessation of a chronic use produces dysphoria [7]. The non-medical opioid use is a major public health challenge, making opioids the second most used

**Keywords:** opioid, methadone, buprenorphine, naltrexone, naloxone

### **Chapter 6**

*Opioids - From Analgesic Use to Addiction*

cocaine cues through actions in the nucleus accumbens. The Journal of Neuroscience. 2010;**30**:10526-10533. DOI: 10.1523/JNEUROSCI.2523-10.2010 and glucocorticoids. Trends in Endocrinology and Metabolism. 2008;**19**:175-180. DOI: 10.1016/j.

[94] Choi DC, Furai AR, Evanson NK, Ostrander MM, Ulrich-Lai YM, Herman JP. Bed nucleus of the stria terminalis subregions differentially regulates hypothalamic-pituitary-adrenal axis activity: Implications for the integration

of limbic inputs. The Journal of

Neuroscience. 2007;**27**:2025-2034. DOI: 10.1523/JNEUROSCI.4301-06.2007

tem.2008.01.009

[87] Myers KM, Carlezon WA Jr. D-cycloserine facilitates extinction of naloxone-induced conditioned place aversion in morphine-dependent rats. Biological Psychiatry. 2010;**67**:85-87. DOI: 10.1016/j.biopsych.2009.08.015

[88] Solecki W, Turek A, Kubik J, Przewlocki R. Motivational effects of opiates in conditioned place preference and aversion paradigm-a study in three inbred strains of mice. Psychopharmacology. 2009;**207**:245-255.

DOI: 10.1007/s00213-009-1672-7

[89] Ueno K, Maeda T, Kiguchi N, Kobayashi Y, Ozaki M, Kishioka S. Availability of serum corticosterone level for quantitative evaluation of morphine withdrawal in mice. Drug Discoveries & Therapeutics. 2011;**5**:71-75.

DOI: 10.5582/ddt.2011.v5.2.71

pnas.0506999102

[91] Harris GC, Aston-Jones

withdrawal. Behavioural Brain Research. 2007;**176**:251-258. DOI:

[92] Koob GF. A role for brain stress system in addiction. Neuron. 2008;**59**:11-34. DOI: 10.1016/j.

[93] Bornstein SR, Engeland WC, Ehrhart-Bornstein ME, Herman JP. Dissociation of ACTH

10.1016/j.bbr.2006.10.012

neuron.2008.06.012

G. Activation in extended amygdale corresponds to alter hedonic

processing during protracted morphine

[90] Contarino A, Papaleo F. The

corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal. Proceedings of the National Academy of Sciences of the United States of America. 2005;**102**:18649-18654. DOI: 10.1073/

**72**

## Present and Future Pharmacological Treatments for Opioid Addiction

*Maria Carmen Blanco-Gandía, Sandra Montagud-Romero and Marta Rodríguez-Arias*

### **Abstract**

When treating opioid addiction, multidisciplinary treatment is highly recommended, but pharmacotherapy plays a key role. Although the ideal goal is to achieve complete abstinence, an elevated percentage of opioid addicts requires maintenance substitution therapy. In the first section of this chapter, we will focus on the current pharmacological interventions to treat opioid addiction, such as methadone, buprenorphine, and naltrexone. Thanks to these medications, people are able to go back to their normal lives, by preventing withdrawal symptoms, reducing craving, and increasing their adherence to psychotherapy. In the second section, based on the evidence that addiction induces neuroadaptive changes in several neurotransmission systems, we focus on the wide range of possible pharmacological developments at the preclinical and clinical levels, which in recent years have increased considerably.

**Keywords:** opioid, methadone, buprenorphine, naltrexone, naloxone

### **1. Introduction**

Addiction is a chronic and multifactorial disorder characterized by compulsive drug seeking and use, despite its harmful consequences. Chronic opioid use induces profound molecular and behavioral changes, inducing long-lasting changes in brain plasticity [1]. During the use of the drug, reward and motivation circuits are modified, and new learning and memories are created in relation to the pleasurable effects of the drug and the context in which it is consumed [2]. These memories will later be responsible for the vulnerability to relapse even after a long period of withdrawal. In order to restructure these memories and avoid relapse and craving to opioids, the first recommended approach currently consists in combining psychotherapy with pharmacological substitution therapy [3]. Opioid addiction is currently a major medical and social problem, and its abuse and recreational use have been declared an epidemic in the USA [4, 5], with more than 90 people dying from an opioid overdose every day [6].

Opioids are highly addictive because they induce euphoria (positive reinforcement) and the cessation of a chronic use produces dysphoria [7]. The non-medical opioid use is a major public health challenge, making opioids the second most used illicit drug in the USA [8].

The use of opioids has increased 10- to 14-fold in the last 20 years, including those taken under supervision and recreational use [9].

In relation to this, opioids are one of the most commonly misused medications. Although it is usually prescribed to treat pain, its abuse has serious medical consequences. According to NIDA (National Institute on Drug Abuse, NIH), misuse of prescription drugs is defined as taking a medication in a manner or dose different than has been prescribed, either for a medical complaint, such as pain, or to feel euphoria [2]. The number of opioid prescriptions has increased significantly since the early 1990s [10], with this easier access to the drug being one of the reasons for the high prevalence of opioid misuse [9]. However, other factors can contribute to the problem, such as the lack of information about the addictive properties of prescription opioids, which are perceived as less harmful than illicit opioids [11, 12]. Regardless of the primary causes, there has been a dramatic increase in the number of treatment admissions for addictive disorders related to prescription opioids, as well as the associated overdose deaths in the past 15 years [8, 13, 14].

Pharmacological treatments are essential for initiating and sustaining effective patient-, public health, and system-level interventions to reduce opioidrelated morbidity and mortality [15]. In the specific case of opioid use disorders, pharmacotherapy is strongly recommended as a part of an integrated approach, also including psychosocial interventions, psychotherapy, or relapse prevention programs [16]. Until the 1960s, the opioid addiction treatment was only oriented towards abstinence, but then the potential action of methadone as a maintenance treatment for opioid addiction was evaluated [17]. Currently, although complete abstinence continues to be the best possible outcome, the most common option is life-long substitution therapy. While the currently approved medications improve the outcomes, relapse rates are still high, and pharmacotherapy is not effective in all patients [18].

The final goal of the treatment is to reduce the risk of illicit opioid use, overdose or infections, as well as the general improvement of the individuals' quality of life [15]. The available pharmacological interventions prevent the appearance of withdrawal symptoms and reduce craving, also increasing adherence to the psychotherapy. First, we will address the three different approved drugs on the market [19]. Although the rate of success, measured by maintenance of abstinence, has been greatly improved with the existing treatments, there is still room for further improvement. In a second part of this chapter, we will also refer to new treatments under development, both in preclinical models and in clinical trials. These new drugs are focused on different neurotransmission systems, which are altered by the neuroadaptive changes induced during the addictive process.

### **2. Current approved pharmacological treatments for opioid addiction**

### **2.1 Opioid agonist therapies**

The great percentage of withdrawn patients who relapse into drug use [20] makes opioid maintenance therapy the first-line treatment in most cases. Ideal agents for substitution maintenance therapy are those with a high affinity for μ-type opioid receptors showing long-term action. Methadone and buprenorphine, as potent and long-acting opioid agonists, are usually prescribed for opioid substitution therapy, and both constitute the most effective treatments for opioid dependence [21].

**75**

*Present and Future Pharmacological Treatments for Opioid Addiction*

methadone pharmacotherapy for heroin addiction [22].

chronic diseases, such as insulin-dependent diabetes [32].

pharmacologic effects mainly via agonism of μ-opioid receptor.

Methadone is a safe, efficient, and effective treatment for heroin addiction [22]. This μ-opioid receptor agonist was introduced in the USA by Eli Lilly and Company as an opioid analgesic in 1947. Methadone maintenance treatment began at the Rockefeller Hospital (1965) with the aim to develop an effective and long action pharmacotherapy that targeted opioid receptors. In these initial clinical trials, patients received safe doses (20–40 mg) once a day, and over time, the dose was adjusted to avoid withdrawal symptoms and reduce craving [17]. Since 1964, a great number of studies have documented the safety, efficacy, and effectiveness of

The National Institutes of Health (NIH) at the end of the 1990s supported methadone maintenance pharmacotherapy for heroin addiction. Nowadays, half of the problematic opiate users are under maintenance treatment, with more than 60% receiving methadone [23]. Elevated retention rates with a noteworthy decrease of illicit opiate use have been observed under methadone maintenance treatment [24–27]. In addition, there are reductions of other associated problems such as intravenous drug use, crime [28–30], and improvement of social functioning [31]. Later studies reported that prolonged methadone maintenance normalized the immune system function in heroin addicts [32], as well as the altered stress response [33]. Methadone is also well suited with performance of complex cognitive tasks [34]. Regarding its efficacy, according to a recent Cochrane meta-analysis, methadone and buprenorphine appear to be equally

Regardless of the positive effects of methadone, one of the main difficulties of methadone maintenance treatment is the stigma accompanying the methadone clinics. In order to solve this, maintenance programs aim to rehabilitate patients by reassigning addicts from a traditional clinic to a medical office for ongoing treatment. The concept of medical maintenance carefully emulates the treatment of

On the other hand, there are specific drug interactions of methadone [36], for example, the antituberculosis agent rifampin or the anticonvulsant phenytoin [37–39]. Methadone can also inhibit gonadotropin-releasing hormones, lowering testosterone levels [40, 41]. Finally, another recognized effect of methadone is the QT prolongation [42]. Patients who undergo prolonged QT intervals must switch to a treatment with buprenorphine, which does not affect it [43]. Several countries, including Germany and Austria, have alternative treatments for opioid maintenance, such as Levomethadone (purified methadone) [44], which exerts its

Buprenorphine and the combination buprenorphine-naloxone were also introduced as a possible treatment for opioid use disorder. This medication is characterized by a better side effect profile, lower abuse potential, and good availability when compared to methadone [3]. Buprenorphine is a μ-receptor partial agonist that can reduce opiate cravings, prevent opiate withdrawal, but at the same time blocks the effects of other more powerful opiates [45]. As partial agonist, buprenorphine presents a safety profile with respect to other μ-opioid-receptor agonists and can be more easily adjusted to the desired effect [46]. Although buprenorphine can be the first-line medication over methadone to treat opioid addiction, as it has considerable less abuse potential, its efficacy is limited when treating severe opioid use disorders. Due to the displacement of a stronger opioid by a weaker

*DOI: http://dx.doi.org/10.5772/intechopen.82443*

*2.1.1 Methadone*

effective [35].

*2.1.2 Buprenorphine*

### *2.1.1 Methadone*

*Opioids - From Analgesic Use to Addiction*

past 15 years [8, 13, 14].

patients [18].

process.

**2.1 Opioid agonist therapies**

those taken under supervision and recreational use [9].

The use of opioids has increased 10- to 14-fold in the last 20 years, including

In relation to this, opioids are one of the most commonly misused medications. Although it is usually prescribed to treat pain, its abuse has serious medical consequences. According to NIDA (National Institute on Drug Abuse, NIH), misuse of prescription drugs is defined as taking a medication in a manner or dose different than has been prescribed, either for a medical complaint, such as pain, or to feel euphoria [2]. The number of opioid prescriptions has increased significantly since the early 1990s [10], with this easier access to the drug being one of the reasons for the high prevalence of opioid misuse [9]. However, other factors can contribute to the problem, such as the lack of information about the addictive properties of prescription opioids, which are perceived as less harmful than illicit opioids [11, 12]. Regardless of the primary causes, there has been a dramatic increase in the number of treatment admissions for addictive disorders related to prescription opioids, as well as the associated overdose deaths in the

Pharmacological treatments are essential for initiating and sustaining effective patient-, public health, and system-level interventions to reduce opioidrelated morbidity and mortality [15]. In the specific case of opioid use disorders, pharmacotherapy is strongly recommended as a part of an integrated approach, also including psychosocial interventions, psychotherapy, or relapse prevention programs [16]. Until the 1960s, the opioid addiction treatment was only oriented towards abstinence, but then the potential action of methadone as a maintenance treatment for opioid addiction was evaluated [17]. Currently, although complete abstinence continues to be the best possible outcome, the most common option is life-long substitution therapy. While the currently approved medications improve the outcomes, relapse rates are still high, and pharmacotherapy is not effective in all

The final goal of the treatment is to reduce the risk of illicit opioid use, overdose or infections, as well as the general improvement of the individuals' quality of life [15]. The available pharmacological interventions prevent the appearance of withdrawal symptoms and reduce craving, also increasing adherence to the psychotherapy. First, we will address the three different approved drugs on the market [19]. Although the rate of success, measured by maintenance of abstinence, has been greatly improved with the existing treatments, there is still room for further improvement. In a second part of this chapter, we will also refer to new treatments under development, both in preclinical models and in clinical trials. These new drugs are focused on different neurotransmission systems, which are altered by the neuroadaptive changes induced during the addictive

**2. Current approved pharmacological treatments for opioid addiction**

The great percentage of withdrawn patients who relapse into drug use [20] makes opioid maintenance therapy the first-line treatment in most cases. Ideal agents for substitution maintenance therapy are those with a high affinity for μ-type opioid receptors showing long-term action. Methadone and buprenorphine,

as potent and long-acting opioid agonists, are usually prescribed for opioid substitution therapy, and both constitute the most effective treatments for opioid

**74**

dependence [21].

Methadone is a safe, efficient, and effective treatment for heroin addiction [22]. This μ-opioid receptor agonist was introduced in the USA by Eli Lilly and Company as an opioid analgesic in 1947. Methadone maintenance treatment began at the Rockefeller Hospital (1965) with the aim to develop an effective and long action pharmacotherapy that targeted opioid receptors. In these initial clinical trials, patients received safe doses (20–40 mg) once a day, and over time, the dose was adjusted to avoid withdrawal symptoms and reduce craving [17]. Since 1964, a great number of studies have documented the safety, efficacy, and effectiveness of methadone pharmacotherapy for heroin addiction [22].

The National Institutes of Health (NIH) at the end of the 1990s supported methadone maintenance pharmacotherapy for heroin addiction. Nowadays, half of the problematic opiate users are under maintenance treatment, with more than 60% receiving methadone [23]. Elevated retention rates with a noteworthy decrease of illicit opiate use have been observed under methadone maintenance treatment [24–27]. In addition, there are reductions of other associated problems such as intravenous drug use, crime [28–30], and improvement of social functioning [31]. Later studies reported that prolonged methadone maintenance normalized the immune system function in heroin addicts [32], as well as the altered stress response [33]. Methadone is also well suited with performance of complex cognitive tasks [34]. Regarding its efficacy, according to a recent Cochrane meta-analysis, methadone and buprenorphine appear to be equally effective [35].

Regardless of the positive effects of methadone, one of the main difficulties of methadone maintenance treatment is the stigma accompanying the methadone clinics. In order to solve this, maintenance programs aim to rehabilitate patients by reassigning addicts from a traditional clinic to a medical office for ongoing treatment. The concept of medical maintenance carefully emulates the treatment of chronic diseases, such as insulin-dependent diabetes [32].

On the other hand, there are specific drug interactions of methadone [36], for example, the antituberculosis agent rifampin or the anticonvulsant phenytoin [37–39]. Methadone can also inhibit gonadotropin-releasing hormones, lowering testosterone levels [40, 41]. Finally, another recognized effect of methadone is the QT prolongation [42]. Patients who undergo prolonged QT intervals must switch to a treatment with buprenorphine, which does not affect it [43]. Several countries, including Germany and Austria, have alternative treatments for opioid maintenance, such as Levomethadone (purified methadone) [44], which exerts its pharmacologic effects mainly via agonism of μ-opioid receptor.

### *2.1.2 Buprenorphine*

Buprenorphine and the combination buprenorphine-naloxone were also introduced as a possible treatment for opioid use disorder. This medication is characterized by a better side effect profile, lower abuse potential, and good availability when compared to methadone [3]. Buprenorphine is a μ-receptor partial agonist that can reduce opiate cravings, prevent opiate withdrawal, but at the same time blocks the effects of other more powerful opiates [45]. As partial agonist, buprenorphine presents a safety profile with respect to other μ-opioid-receptor agonists and can be more easily adjusted to the desired effect [46]. Although buprenorphine can be the first-line medication over methadone to treat opioid addiction, as it has considerable less abuse potential, its efficacy is limited when treating severe opioid use disorders. Due to the displacement of a stronger opioid by a weaker

one, buprenorphine can precipitate withdrawal symptoms [33, 47]. To increase the adherence to this treatment, patients should be at least in mild withdrawal [48].

To avoid diversion, buprenorphine is usually combined with the specific opioid antagonist, naloxone. In 2006, it was introduced in the European market as a sublingual combination tablet. Several works have established the efficacy of buprenorphine-naloxone as a maintenance medication [49–51] not only for prescription opioids but also for heroin addiction [52, 53]. Numerous metaanalyses have determined that buprenorphine produces successful results in heroin dependence, with no deficiency with respect to being abstinent of illicit opioid use [54, 55]. However, methadone was found to be superior to buprenorphine in overall treatment retention [56]. Buprenorphine therapy not only improves the overall individuals' quality of life but also decreases overcrowding in emergency departments [57, 58].

From a pharmacological point of view, buprenorphine has important advantages over methadone besides the lower risk of overdose [41, 59]. It is preferable for treatment of opioid dependence in those patients with HIV/AIDS [60, 61] and for pregnant opioid users [62]. On the other hand, when buprenorphine is combined with respiratory depressants, such as alcohol or benzodiazepines, it results in sedation, coma, or even death [63]. Furthermore, patients who do not know about the pharmacology of buprenorphine and use additional opioids seeking a "high" are at risk of an overdose when the effects of buprenorphine wear off [55, 64, 65].

### **2.2 Opiate antagonist therapies**

The antagonist therapy blocks or reduces a biological response by binding to and blocking a receptor rather than activating it like an agonist. Naloxone and naltrexone, the opioid antagonist treatments most accepted and commonly used, prevent and reverse opioid effects by mainly blocking the μ-opioid receptor. Both are employed for quick detoxification if there is an overdose and to prevent relapse [66]. Naloxone is a short-acting non-selective opioid antagonist that reverses an opioid overdose. Overdose is a common event for those who use opioids and is the leading cause of death in this population [67, 68]. It quickly crosses the bloodbrain barrier and can reverse morphine-induced respiratory depression within 1–2 min [69].

Different studies support the effectiveness of community-based naloxone training and distribution programs in reducing overdose deaths [24, 70, 71]. Naloxone is considered a safe drug to use with little probability of complications, since it has no agonistic activity at the μ-opioid receptor [23]. Since opioid abuse has been declared an epidemic in the USA [4], naloxone has been made more accessible to the relatives of opioid users, which decreases potentially fatal overdoses around 30–40% [72, 73].

Naltrexone is an opioid receptor antagonist that blocks the euphoric and reinforcing effects of opioids consumption, being mainly used for detoxification programs [74–77]. However, the main disadvantage of the use of this antagonist is the low rate of adherence to this treatment, since less than 20% of patients continue opioid antagonist treatments after several months [78]. Nevertheless, with highly motivated patients or dependent people who cannot be included in the methadone program, naltrexone maintenance therapy can be proposed as a successful approach for treating opioid addiction [79]. Furthermore, it has the advantage of not generating tolerance and/or dependency [80]. In the last years, a new intra-muscular depot formulation of naltrexone has been approved, being useful in reducing the days-of-heroin-use and relapse rate compared with a placebo [81, 82]. This depot naltrexone is taken once monthly, and several studies have shown good outcomes compared to placebo in decreasing craving in naltrexone-treated patients [83].

**77**

*Present and Future Pharmacological Treatments for Opioid Addiction*

such as the sublingual film of buprenorphine-naloxone [85].

advances in neuroinflammation and the pharmacogenetics field.

These extended-release naltrexone formulations address the compliance problems that are often found with oral administration [84]. However, a recent comparative study shows that the extended-release naltrexone presents more difficulties in terms of induction and ongoing care with respect to other buprenorphine products,

Nevertheless, to date, the extended-release naltrexone is, together with methadone and buprenorphine, the most recommended pharmacotherapy for opioid use disorders, as it has shown superiority with respect to placebo treatment and coun-

**3. New pharmacological therapies in development of opiate addiction**

Drug addiction induces significant changes in numerous neurotransmission systems [1], which became new therapeutic targets to treat opioid addiction. Therefore, new pharmacological targets are constantly being developed to improve opiate addiction treatment. This second part of the review will offer an overview of the most promising agents under development and we will also discuss the recent

With the aim of increasing the efficacy and adherence of treatments, numerous studies are testing new approaches to the currently approved medications. For example, the newest buprenorphine subdermal implant called probuphine [88], which was approved by the FDA in May 2016, is prescribed to those patients who have achieved a sustained clinical stability with low-to-moderate doses of a transmucosal buprenorphine-containing product.This implant guarantees nonfluctuating blood levels of buprenorphine continuously for 6 months improving

There is growing interest in the slow-release oral morphine (SROM), as a potential effective candidate for maintenance treatment [90–92]. This medication is given once daily, and it suits those individuals who cannot tolerate methadone, respond poorly to other available treatments, or show a prolonged QT [93–95]. However, the last Cochrane meta-analysis reported that there is not enough evidence to confirm the effectiveness of SROM for opioid maintenance, as only three inconclusive stud-

Tramadol, a reuptake inhibitor of serotonin and norepinephrine, produces a metabolite that moderately acts as a μ-opioid receptor agonist [97]. Recent clinical trials have demonstrated for tramadol the same level of treatment retention and opioid withdrawal symptom suppression as buprenorphine, suggesting that this is a promising and valuable medication [98, 99]. However, although it has been used in the management of acute withdrawal, its use for maintenance treatment as a harm reduction approach has not been assessed systematically. A recent pilot study of tramadol on long-term maintenance in patients with opioid use disorders showed that most of them were able to achieve and maintain abstinence for at least 6 months [100].

It is well known that dopamine (DA) neurotransmission is a common mechanism of drugs of abuse, although the use of DA compounds has not been successful [22]. Numerous preclinical studies have tested the efficacy of different DA antagonists. Acute administration of the DA D3 receptor antagonist SB277011

*DOI: http://dx.doi.org/10.5772/intechopen.82443*

**3.1 Drugs acting on opioid receptors**

patient compliance [89].

**3.2 Dopaminergic compounds**

ies exist [96].

seling [83, 86, 87].

*Present and Future Pharmacological Treatments for Opioid Addiction DOI: http://dx.doi.org/10.5772/intechopen.82443*

*Opioids - From Analgesic Use to Addiction*

departments [57, 58].

**2.2 Opiate antagonist therapies**

1–2 min [69].

one, buprenorphine can precipitate withdrawal symptoms [33, 47]. To increase the adherence to this treatment, patients should be at least in mild withdrawal [48]. To avoid diversion, buprenorphine is usually combined with the specific opioid antagonist, naloxone. In 2006, it was introduced in the European market as a sublingual combination tablet. Several works have established the efficacy of buprenorphine-naloxone as a maintenance medication [49–51] not only for prescription opioids but also for heroin addiction [52, 53]. Numerous meta-

analyses have determined that buprenorphine produces successful results in heroin dependence, with no deficiency with respect to being abstinent of illicit opioid use [54, 55]. However, methadone was found to be superior to buprenorphine in overall treatment retention [56]. Buprenorphine therapy not only improves the overall individuals' quality of life but also decreases overcrowding in emergency

From a pharmacological point of view, buprenorphine has important advantages

The antagonist therapy blocks or reduces a biological response by binding to and blocking a receptor rather than activating it like an agonist. Naloxone and naltrexone, the opioid antagonist treatments most accepted and commonly used, prevent and reverse opioid effects by mainly blocking the μ-opioid receptor. Both are employed for quick detoxification if there is an overdose and to prevent relapse [66]. Naloxone is a short-acting non-selective opioid antagonist that reverses an opioid overdose. Overdose is a common event for those who use opioids and is the leading cause of death in this population [67, 68]. It quickly crosses the bloodbrain barrier and can reverse morphine-induced respiratory depression within

Different studies support the effectiveness of community-based naloxone training and distribution programs in reducing overdose deaths [24, 70, 71]. Naloxone is considered a safe drug to use with little probability of complications, since it has no agonistic activity at the μ-opioid receptor [23]. Since opioid abuse has been declared an epidemic in the USA [4], naloxone has been made more accessible to the relatives of opioid users, which decreases potentially fatal overdoses around 30–40% [72, 73]. Naltrexone is an opioid receptor antagonist that blocks the euphoric and reinforcing effects of opioids consumption, being mainly used for detoxification programs [74–77]. However, the main disadvantage of the use of this antagonist is the low rate of adherence to this treatment, since less than 20% of patients continue opioid antagonist treatments after several months [78]. Nevertheless, with highly motivated patients or dependent people who cannot be included in the methadone program, naltrexone maintenance therapy can be proposed as a successful approach for treating opioid addiction [79]. Furthermore, it has the advantage of not generating tolerance and/or dependency [80]. In the last years, a new intra-muscular depot formulation of naltrexone has been approved, being useful in reducing the days-of-heroin-use and relapse rate compared with a placebo [81, 82]. This depot naltrexone is taken once monthly, and several studies have shown good outcomes compared to placebo in decreasing craving in naltrexone-treated patients [83].

over methadone besides the lower risk of overdose [41, 59]. It is preferable for treatment of opioid dependence in those patients with HIV/AIDS [60, 61] and for pregnant opioid users [62]. On the other hand, when buprenorphine is combined with respiratory depressants, such as alcohol or benzodiazepines, it results in sedation, coma, or even death [63]. Furthermore, patients who do not know about the pharmacology of buprenorphine and use additional opioids seeking a "high" are at risk of an overdose when the effects of buprenorphine wear off [55, 64, 65].

**76**

These extended-release naltrexone formulations address the compliance problems that are often found with oral administration [84]. However, a recent comparative study shows that the extended-release naltrexone presents more difficulties in terms of induction and ongoing care with respect to other buprenorphine products, such as the sublingual film of buprenorphine-naloxone [85].

Nevertheless, to date, the extended-release naltrexone is, together with methadone and buprenorphine, the most recommended pharmacotherapy for opioid use disorders, as it has shown superiority with respect to placebo treatment and counseling [83, 86, 87].

### **3. New pharmacological therapies in development of opiate addiction**

Drug addiction induces significant changes in numerous neurotransmission systems [1], which became new therapeutic targets to treat opioid addiction. Therefore, new pharmacological targets are constantly being developed to improve opiate addiction treatment. This second part of the review will offer an overview of the most promising agents under development and we will also discuss the recent advances in neuroinflammation and the pharmacogenetics field.

### **3.1 Drugs acting on opioid receptors**

With the aim of increasing the efficacy and adherence of treatments, numerous studies are testing new approaches to the currently approved medications. For example, the newest buprenorphine subdermal implant called probuphine [88], which was approved by the FDA in May 2016, is prescribed to those patients who have achieved a sustained clinical stability with low-to-moderate doses of a transmucosal buprenorphine-containing product.This implant guarantees nonfluctuating blood levels of buprenorphine continuously for 6 months improving patient compliance [89].

There is growing interest in the slow-release oral morphine (SROM), as a potential effective candidate for maintenance treatment [90–92]. This medication is given once daily, and it suits those individuals who cannot tolerate methadone, respond poorly to other available treatments, or show a prolonged QT [93–95]. However, the last Cochrane meta-analysis reported that there is not enough evidence to confirm the effectiveness of SROM for opioid maintenance, as only three inconclusive studies exist [96].

Tramadol, a reuptake inhibitor of serotonin and norepinephrine, produces a metabolite that moderately acts as a μ-opioid receptor agonist [97]. Recent clinical trials have demonstrated for tramadol the same level of treatment retention and opioid withdrawal symptom suppression as buprenorphine, suggesting that this is a promising and valuable medication [98, 99]. However, although it has been used in the management of acute withdrawal, its use for maintenance treatment as a harm reduction approach has not been assessed systematically. A recent pilot study of tramadol on long-term maintenance in patients with opioid use disorders showed that most of them were able to achieve and maintain abstinence for at least 6 months [100].

### **3.2 Dopaminergic compounds**

It is well known that dopamine (DA) neurotransmission is a common mechanism of drugs of abuse, although the use of DA compounds has not been successful [22]. Numerous preclinical studies have tested the efficacy of different DA antagonists. Acute administration of the DA D3 receptor antagonist SB277011

reduces the reinforcing effects of different drugs of abuse and diminishes opiate withdrawal syndrome [101]. The well-known antipsychotics, aripiprazole (partial DAD2 and 5HT1A agonist and a 5HT2A antagonist) and risperidone (atypical antipsychotic), block context-dependent induced relapse. Risperidone also inhibits reinstatement into heroin seeking due to environmental cues but fails to block relapse induced by priming doses [102]. In the same line, aripiprazole inhibits the conditioned place preference (CPP) induced by morphine [103]. An ongoing clinical trial is evaluating aripiprazole effects to prevent relapse to cocaine use in patients being treated with methadone, as they could return to cocaine consumption, even when they are involved in a drug treatment program [104].

### **3.3 Glutamatergic compounds**

Preclinical studies show that reinstatement of morphine CPP is mainly mediated through glutamatergic neurotransmission [105]. NMDA receptors modulate nociceptive signals in conjunction with opioid receptors, and after continuous morphine treatment, both receptors suffer a desensitization, which mediate analgesic tolerance [22]. Therefore, NMDA receptor antagonists can prevent the development of morphine tolerance. Ifenprodil, an NMDA antagonist, prevents the development, maintenance, and reinstatement of morphine-induced CPP, as well as reinstatement of heroin-seeking self-administration [106].

Another well-known NMDA antagonist is memantine. Animal and human studies have shown positive results in reducing opiate withdrawal and preventing relapse [107–109]. However, clinical trials have not found significant differences in treatment retention, heroin consumption, or craving with respect to placebo [110]. Although memantine administered in combination with naltrexone can improve the emerging symptoms during the early phase of treatment, this combination did not induce significant improvement in preventing relapse [111].

The nitric oxide synthase (NOS) is a neural retrograde messenger molecule involved in several opioid effects. It has been reported that NOS upregulation takes place during the development of opioid dependence [112] and its inhibition blocks opioid dependence [113, 114]. In addition, administration of NOS inhibitors diminishes the development of morphine-induced CPP [106].

### **3.4 GABA compounds**

Baclofen is a GABA-B receptor agonist approved for spasticity treatment, and early preclinical studies suggested that it could promote abstinence from a variety of drugs of abuse [115], such as cocaine, ethanol, nicotine, and methamphetamine [116–119]. Baclofen also reduces morphine withdrawal signs in morphinedependent animals [120, 121] and disrupts reconsolidation of conditioned reward, facilitating the extinction of the morphine-induced CPP [122]. Assadi and coworkers [123] performed a clinical trial to evaluate the possible benefit of baclofen in the maintenance treatment of opioid addicts and found that the baclofen group presented increased treatment retention being superior to placebo in terms of opiate withdrawal syndrome and depressive symptoms.

An effective add-on therapy combined with methadone or buprenorphine is pregabalin and gabapentin, which are approved for treatment of epilepsy, neuropathic pain, or fibromyalgia [124]. These medications do not act directly on GABA receptors or transporters [125] but modulate the α2-delta subunit of calcium channels, preventing the release of neurotransmitters like glutamate [126]. Both medications prevent opioid tolerance and dependence and reduce withdrawal symptoms in humans and preclinical models [127–129].

**79**

*Present and Future Pharmacological Treatments for Opioid Addiction*

Numerous studies have demonstrated that the cholinergic system is also implicated in opioid addiction, as chronic morphine administration is associated with changes in gene expression in the cholinergic system, and it increases cholinergic neurons in the laterodorsal tegmental nucleus. Administration of nicotinic antagonists reduces withdrawal symptoms in rodents [130], which suggests that nicotine receptors might be a potential pharmacotherapeutic target for opioid detoxification. Furthermore, a relatively recent study evaluated the role of the α4β2 nicotinic receptors as a potential therapeutic target to treat morphine dependence [131]. A recent clinical trial has evaluated the effects of varenicline, a α4β2 partial agonist and α7 full agonist, usually employed for smoking cessation. Varenicline was effective in opioid detoxification patients, as opioid withdrawal scores decrease with

Cholinesterase inhibitors, currently used to treat Alzheimer's disease, including donepezil, rivastigmine, and galantamine, increase cholinergic activity and can be potential therapeutic targets in opioid abuse and dependence treatments [132]. Preclinical models have demonstrated that these cholinesterase inhibitors prevented morphine tolerance and attenuated the acquisition and expression

There are many studies suggesting the potential action of the endocannabinoid system in opioid dependence [134, 135]. Cannabidiol is a natural active metabolite of the *Cannabis sativa* plant, which is currently being explored for its potential anti-addiction properties [135]. It is the second most abundant cannabinoid present in the plant [136], and interestingly, it does not bind directly to cannabinoid receptors but acts as an inverse agonist at both types CB1 and CB2 [137]. Regarding this, cannabidiol has been shown to attenuate the cue-induced reinstatement of heroin seeking [138] and reduces the rewarding properties of morphine in rodents [139]. There is currently a clinical trial examining the effects of cannabidiol on drug craving in abstinent heroin-dependent subjects (ClinicalTrial.Gov identifier: NCT02539823). In addition, cannabidiol, when combined with a potent opioid like fentanyl, is well tolerated, confirming that cannabidiol would be safe in the case of

The neuroimmune response is an important but relatively poorly understood process in the development of drug addiction. Research is now setting up opportunities for the development of new pharmacotherapies targeting neuroimmune dysfunction. Opioids induce direct and indirect adaptations in the peripheral and central immune systems [141] with a clear relationship between opioid dependence and inflammatory processes [142]. Opioids, such as morphine and heroin, act directly on macrophages and lymphocytes, which produce changes in the CNS, resulting in neurotoxicity [143–145]. Preclinical models show that chronic morphine treatment increases proinflammatory cytokine levels and overactivates the glia [146, 147]. The consequences include dendrite atrophy, abnormal neurogenesis, and neurodegeneration [148]. To sum up, opioids act to generate the release of proinflammatory cytokines, which induce the activation of the inflammatory response, and finally, this response induces changes in the architecture and functioning of the brain. Neuroinflammation derived from opioid consumption is implicated in

*DOI: http://dx.doi.org/10.5772/intechopen.82443*

respect to those patients receiving a placebo [131].

**3.5 Cholinergic compounds**

of morphine CPP [133].

**3.6 Cannabinoid compounds**

a relapse in abstinent heroin abusers [140].

**3.7 Neuroinflammation**

### **3.5 Cholinergic compounds**

*Opioids - From Analgesic Use to Addiction*

**3.3 Glutamatergic compounds**

**3.4 GABA compounds**

of heroin-seeking self-administration [106].

reduces the reinforcing effects of different drugs of abuse and diminishes opiate withdrawal syndrome [101]. The well-known antipsychotics, aripiprazole (partial DAD2 and 5HT1A agonist and a 5HT2A antagonist) and risperidone (atypical antipsychotic), block context-dependent induced relapse. Risperidone also inhibits reinstatement into heroin seeking due to environmental cues but fails to block relapse induced by priming doses [102]. In the same line, aripiprazole inhibits the conditioned place preference (CPP) induced by morphine [103]. An ongoing clinical trial is evaluating aripiprazole effects to prevent relapse to cocaine use in patients being treated with methadone, as they could return to cocaine consump-

Preclinical studies show that reinstatement of morphine CPP is mainly mediated through glutamatergic neurotransmission [105]. NMDA receptors modulate nociceptive signals in conjunction with opioid receptors, and after continuous morphine treatment, both receptors suffer a desensitization, which mediate analgesic tolerance [22]. Therefore, NMDA receptor antagonists can prevent the development of morphine tolerance. Ifenprodil, an NMDA antagonist, prevents the development, maintenance, and reinstatement of morphine-induced CPP, as well as reinstatement

Another well-known NMDA antagonist is memantine. Animal and human studies have shown positive results in reducing opiate withdrawal and preventing relapse [107–109]. However, clinical trials have not found significant differences in treatment retention, heroin consumption, or craving with respect to placebo [110]. Although memantine administered in combination with naltrexone can improve the emerging symptoms during the early phase of treatment, this combination did

The nitric oxide synthase (NOS) is a neural retrograde messenger molecule involved in several opioid effects. It has been reported that NOS upregulation takes place during the development of opioid dependence [112] and its inhibition blocks opioid dependence [113, 114]. In addition, administration of NOS inhibitors

Baclofen is a GABA-B receptor agonist approved for spasticity treatment, and early preclinical studies suggested that it could promote abstinence from a variety of drugs of abuse [115], such as cocaine, ethanol, nicotine, and methamphetamine [116–119]. Baclofen also reduces morphine withdrawal signs in morphinedependent animals [120, 121] and disrupts reconsolidation of conditioned reward, facilitating the extinction of the morphine-induced CPP [122]. Assadi and coworkers [123] performed a clinical trial to evaluate the possible benefit of baclofen in the maintenance treatment of opioid addicts and found that the baclofen group presented increased treatment retention being superior to placebo in terms of opiate

An effective add-on therapy combined with methadone or buprenorphine is pregabalin and gabapentin, which are approved for treatment of epilepsy, neuropathic pain, or fibromyalgia [124]. These medications do not act directly on GABA receptors or transporters [125] but modulate the α2-delta subunit of calcium channels, preventing the release of neurotransmitters like glutamate [126]. Both medications prevent opioid tolerance and dependence and reduce withdrawal symptoms in

not induce significant improvement in preventing relapse [111].

diminishes the development of morphine-induced CPP [106].

withdrawal syndrome and depressive symptoms.

humans and preclinical models [127–129].

tion, even when they are involved in a drug treatment program [104].

**78**

Numerous studies have demonstrated that the cholinergic system is also implicated in opioid addiction, as chronic morphine administration is associated with changes in gene expression in the cholinergic system, and it increases cholinergic neurons in the laterodorsal tegmental nucleus. Administration of nicotinic antagonists reduces withdrawal symptoms in rodents [130], which suggests that nicotine receptors might be a potential pharmacotherapeutic target for opioid detoxification. Furthermore, a relatively recent study evaluated the role of the α4β2 nicotinic receptors as a potential therapeutic target to treat morphine dependence [131]. A recent clinical trial has evaluated the effects of varenicline, a α4β2 partial agonist and α7 full agonist, usually employed for smoking cessation. Varenicline was effective in opioid detoxification patients, as opioid withdrawal scores decrease with respect to those patients receiving a placebo [131].

Cholinesterase inhibitors, currently used to treat Alzheimer's disease, including donepezil, rivastigmine, and galantamine, increase cholinergic activity and can be potential therapeutic targets in opioid abuse and dependence treatments [132]. Preclinical models have demonstrated that these cholinesterase inhibitors prevented morphine tolerance and attenuated the acquisition and expression of morphine CPP [133].

### **3.6 Cannabinoid compounds**

There are many studies suggesting the potential action of the endocannabinoid system in opioid dependence [134, 135]. Cannabidiol is a natural active metabolite of the *Cannabis sativa* plant, which is currently being explored for its potential anti-addiction properties [135]. It is the second most abundant cannabinoid present in the plant [136], and interestingly, it does not bind directly to cannabinoid receptors but acts as an inverse agonist at both types CB1 and CB2 [137]. Regarding this, cannabidiol has been shown to attenuate the cue-induced reinstatement of heroin seeking [138] and reduces the rewarding properties of morphine in rodents [139]. There is currently a clinical trial examining the effects of cannabidiol on drug craving in abstinent heroin-dependent subjects (ClinicalTrial.Gov identifier: NCT02539823). In addition, cannabidiol, when combined with a potent opioid like fentanyl, is well tolerated, confirming that cannabidiol would be safe in the case of a relapse in abstinent heroin abusers [140].

### **3.7 Neuroinflammation**

The neuroimmune response is an important but relatively poorly understood process in the development of drug addiction. Research is now setting up opportunities for the development of new pharmacotherapies targeting neuroimmune dysfunction. Opioids induce direct and indirect adaptations in the peripheral and central immune systems [141] with a clear relationship between opioid dependence and inflammatory processes [142]. Opioids, such as morphine and heroin, act directly on macrophages and lymphocytes, which produce changes in the CNS, resulting in neurotoxicity [143–145]. Preclinical models show that chronic morphine treatment increases proinflammatory cytokine levels and overactivates the glia [146, 147]. The consequences include dendrite atrophy, abnormal neurogenesis, and neurodegeneration [148]. To sum up, opioids act to generate the release of proinflammatory cytokines, which induce the activation of the inflammatory response, and finally, this response induces changes in the architecture and functioning of the brain. Neuroinflammation derived from opioid consumption is implicated in

tolerance and dependence processes based on results obtained in animal models [149–151]. Anti-inflammatory cytokines, such as the IL-10, which are well tolerated and safe in other inflammatory diseases, could be used as pharmacotherapy in addiction [152]. For example, gabapentin upregulates the anti-inflammatory cytokine IL-10 in rats [128], thus reducing inflammation. Ibudilast prevents glial cell activation, inhibiting production of proinflammatory cytokines (IL1β, IL-6, TNF-α), and increases the secretion of anti-inflammatory mediators like IL-10 [153]. Clinical trials are currently evaluating if this medication, or other glial activation inhibitors, can prevent opioid withdrawal symptoms [154].

On the other hand, peroxisome proliferator-activated receptors (PPARs) mediate anti-inflammatory and neuroprotective processes [155]. Specifically, PPARγ is strongly implicated in reward processing and motivation [156], as they are located in VTA DA neurons and modulate DA release [157], which suggests its potential role in addiction. Currently, preclinical studies have tested the PPAR-γ agonist pioglitazone, an anti-inflammatory medication, as a treatment for opioid dependence, attenuating morphine withdrawal syndrome in rats [158].

### **3.8 Pharmacogenetics and epigenetics**

Pharmacogenetics focuses on selecting the most adequate treatment for specific patients, based on their genetic profile and thereby increasing the therapeutic action of the medication. Its goal is the discovery of gene interactions that increase the success rate of treatments [22]. There are variants of gene-encoding proteins implicated in opioid pharmacokinetics and pharmacodynamics that make the patient respond better or worse to a specific treatment. Most studies focus on genes related to the therapeutic response to methadone and buprenorphine [159]. For example, two gene interactions are determinant for the response to methadone. First, there is the ABCB1, the gene encoding the P-glycoprotein efflux transporter, of which methadone is a substrate. People with variants of this gene (subjects with a wild-type and 61A haplotype combination or homozygous for the 61A) show lower methadone requirements. On the other hand, people with the variant 118A/A in μ-opioid receptor 1 gene (MOR1) show higher methadone requirements [160]. Regarding buprenorphine, the frequency of the gene polymorphism (SLC6A3/DAT1) allele 10 in the DA transporter is much higher in non-responder individuals [161]. These studies reveal the relevance of considering genetic variants when considering treatments with methadone or buprenorphine.

Currently, it is known that it is not only the polymorphisms that we inherit but also how they are expressed, what really matters in genetics. Epigenetics studies the reversible modifications to chromatin and their potent effects on gene expression regulation. Biochemical modifications, such as DNA methylation, histone modification, or micro-RNA expression, can change the pattern of the cell's gene expression [162]. Consequently, such epigenetic changes can modify drug efficacy and its adverse effects, being necessary to take them into account in clinical pharmacology [163]. Currently, the role of epigenetics in personalized pharmacotherapy has been under-explored [164]. This field of research has increased scientific interest in the last years, as changes in DNA methylation or histone modifications alter gene expression, which affects reward, craving, and relapse [165]. For example, in opiate addiction, several changes have been reported in the μ-opioid receptor 1 (OPRM1) gene expression due to the hypermethylation of this gene's promoter [166, 167]. Increased DNA methylation can be a predisposing factor for the vulnerability to heroin addiction or it can be a consequence of it. This is a new and exciting unexplored field that could offer promising results in future years.

**81**

**Author details**

opiate addiction.

language editing.

None.

**Conflict of interest**

**Acknowledgements**

Marta Rodríguez-Arias\*

provided the original work is properly cited.

*Present and Future Pharmacological Treatments for Opioid Addiction*

Opioid addiction is a chronic relapsing brain disease, being a major medical and social problem. In the past 12 years, several countries are suffering a rise in opioid consumption, not only in its recreative use but also in opioid prescriptions and related misuse and abuse [5]. The high rate of relapse observed in opioid addicts forces the use of maintenance therapy with substitution opiates to reduce damage and to avoid the consumption of illegal opioids, such as heroin. Although the currently approved pharmacotherapies for opioid addiction are effective and encourage patients to stay in treatment, there is still much room for improvement [168]. Methadone, buprenorphine, and extended-release naltrexone are currently the most effective treatments to attenuate the illicit intake of opioids and, together with psychosocial therapy, constitute the best combination to succeed in the treatment [18]. The number of new pharmacological targets is constantly increasing, but frequently, initially promising preclinical studies result in failure in the clinical trials. However, we should be optimistic, since great advances have been made in recent years, but much remains to be improved in a disease as important and complex as

*DOI: http://dx.doi.org/10.5772/intechopen.82443*

**4. Conclusion and future directions**

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Maria Carmen Blanco-Gandía, Sandra Montagud-Romero and

\*Address all correspondence to: marta.rodriguez@uv.es

Unit of Research Psychobiology of Drug Dependence, Department of

Psychobiology, Facultad de Psicología, Universitat de Valencia, Valencia, Spain

This work was supported by Ministerio de Economía y Competitividad (MINECO), Dirección General de Investigación PSI2014-51847-R and PSI2017- 83023-R. Instituto de Salud Carlos III, Red de Trastornos Adictivos (RTA) RD12/0028/0005 y RD16/0017/0007 and Unión Europea, Fondos FEDER "una manera de hacer Europa." We wish to thank Guillermo Chulia for his English

### **4. Conclusion and future directions**

*Opioids - From Analgesic Use to Addiction*

tolerance and dependence processes based on results obtained in animal models [149–151]. Anti-inflammatory cytokines, such as the IL-10, which are well tolerated and safe in other inflammatory diseases, could be used as pharmacotherapy in addiction [152]. For example, gabapentin upregulates the anti-inflammatory cytokine IL-10 in rats [128], thus reducing inflammation. Ibudilast prevents glial cell activation, inhibiting production of proinflammatory cytokines (IL1β, IL-6, TNF-α), and increases the secretion of anti-inflammatory mediators like IL-10 [153]. Clinical trials are currently evaluating if this medication, or other glial activa-

On the other hand, peroxisome proliferator-activated receptors (PPARs) mediate anti-inflammatory and neuroprotective processes [155]. Specifically, PPARγ is strongly implicated in reward processing and motivation [156], as they are located in VTA DA neurons and modulate DA release [157], which suggests its potential role in addiction. Currently, preclinical studies have tested the PPAR-γ agonist pioglitazone, an anti-inflammatory medication, as a treatment for opioid dependence,

Pharmacogenetics focuses on selecting the most adequate treatment for specific patients, based on their genetic profile and thereby increasing the therapeutic action of the medication. Its goal is the discovery of gene interactions that increase the success rate of treatments [22]. There are variants of gene-encoding proteins implicated in opioid pharmacokinetics and pharmacodynamics that make the patient respond better or worse to a specific treatment. Most studies focus on genes related to the therapeutic response to methadone and buprenorphine [159]. For example, two gene interactions are determinant for the response to methadone. First, there is the ABCB1, the gene encoding the P-glycoprotein efflux transporter, of which methadone is a substrate. People with variants of this gene (subjects with a wild-type and 61A haplotype combination or homozygous for the 61A) show lower methadone requirements. On the other hand, people with the variant 118A/A in μ-opioid receptor 1 gene (MOR1) show higher methadone requirements [160]. Regarding buprenorphine, the frequency of the gene polymorphism (SLC6A3/DAT1) allele 10 in the DA transporter is much higher in non-responder individuals [161]. These studies reveal the relevance of considering genetic variants when considering treatments with methadone or

Currently, it is known that it is not only the polymorphisms that we inherit but also how they are expressed, what really matters in genetics. Epigenetics studies the reversible modifications to chromatin and their potent effects on gene expression regulation. Biochemical modifications, such as DNA methylation, histone modification, or micro-RNA expression, can change the pattern of the cell's gene expression [162]. Consequently, such epigenetic changes can modify drug efficacy and its adverse effects, being necessary to take them into account in clinical pharmacology [163]. Currently, the role of epigenetics in personalized pharmacotherapy has been under-explored [164]. This field of research has increased scientific interest in the last years, as changes in DNA methylation or histone modifications alter gene expression, which affects reward, craving, and relapse [165]. For example, in opiate addiction, several changes have been reported in the μ-opioid receptor 1 (OPRM1) gene expression due to the hypermethylation of this gene's promoter [166, 167]. Increased DNA methylation can be a predisposing factor for the vulnerability to heroin addiction or it can be a consequence of it. This is a new and exciting unex-

plored field that could offer promising results in future years.

tion inhibitors, can prevent opioid withdrawal symptoms [154].

attenuating morphine withdrawal syndrome in rats [158].

**3.8 Pharmacogenetics and epigenetics**

**80**

buprenorphine.

Opioid addiction is a chronic relapsing brain disease, being a major medical and social problem. In the past 12 years, several countries are suffering a rise in opioid consumption, not only in its recreative use but also in opioid prescriptions and related misuse and abuse [5]. The high rate of relapse observed in opioid addicts forces the use of maintenance therapy with substitution opiates to reduce damage and to avoid the consumption of illegal opioids, such as heroin. Although the currently approved pharmacotherapies for opioid addiction are effective and encourage patients to stay in treatment, there is still much room for improvement [168]. Methadone, buprenorphine, and extended-release naltrexone are currently the most effective treatments to attenuate the illicit intake of opioids and, together with psychosocial therapy, constitute the best combination to succeed in the treatment [18]. The number of new pharmacological targets is constantly increasing, but frequently, initially promising preclinical studies result in failure in the clinical trials. However, we should be optimistic, since great advances have been made in recent years, but much remains to be improved in a disease as important and complex as opiate addiction.

### **Acknowledgements**

This work was supported by Ministerio de Economía y Competitividad (MINECO), Dirección General de Investigación PSI2014-51847-R and PSI2017- 83023-R. Instituto de Salud Carlos III, Red de Trastornos Adictivos (RTA) RD12/0028/0005 y RD16/0017/0007 and Unión Europea, Fondos FEDER "una manera de hacer Europa." We wish to thank Guillermo Chulia for his English language editing.

### **Conflict of interest**

None.

### **Author details**

Maria Carmen Blanco-Gandía, Sandra Montagud-Romero and Marta Rodríguez-Arias\* Unit of Research Psychobiology of Drug Dependence, Department of Psychobiology, Facultad de Psicología, Universitat de Valencia, Valencia, Spain

\*Address all correspondence to: marta.rodriguez@uv.es

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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*Opioids - From Analgesic Use to Addiction*

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and Personalized Medicine.

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microglia. Neuropharmacology.

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Neuropsychopharmacology.

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2004;**6**(3):404-411

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*Edited by Pilar Almela Rojo*

Morphine and other opioids are potent analgesic drugs, but their use can lead to complications. Being familiar with the use of this kind of drug can make the difference between obtaining the expected benefit of applied therapy or magnifying the risks to intolerable levels for the patient. Therefore, it is essential for practitioners to achieve adequate training in the management of these drugs based on criteria endorsed by scientific evidence that allows the proper use of these drugs and guarantees the best professional practice every time. Written by expert authors in the field, the purpose of this book is to offer an overview of opioid drugs, from their therapeutic use to the consequences associated.

Published in London, UK © 2020 IntechOpen © PeterHermesFurian / iStock

Opioids - From Analgesic Use to Addiction

Opioids

From Analgesic Use to Addiction

*Edited by Pilar Almela Rojo*