**5. Clinical relevance**

Trigeminal primary afferent neurons have been the focus of intense research also because of their contribution to acute and chronic pain states, and the important role played by trigeminal nociceptive pathways in most clinically significant pain disorders. In response to trigeminal nerve activation, craniofacial pain symptoms can manifest as transient pain conditions as reported with toothaches and headaches, or can transform into more chronic pain conditions such as migraine, temporomandibular joint disorders or trigeminal neuralgia (Durham & Garrett, 2010). Apart from electrical activation, chemical activation of the trigeminal nerve leads to an afferent and efferent release of certain neuropeptides that facilitate peripheral inflammatory responses and causes activation of second-order neurons involved in pain transmission (Buzzi, 2001). Accumulating evidence suggests that CGRP and NO are involved in the underlying pathophysiology of all vascular headaches, the vast majority of which are associated with an inflammatory process. In particular, CGRP, a potent vasodilator and pro-inflammatory agent which is expressed by trigeminal nociceptors, has been identified as a key player in the pathomechanism of migraine headache (McCulloch et al., 1986). Clinical studies have also shown a clear association between the head pain and the release of CGRP, from the trigeminovascular system (for a review, see Edvinsson & Uddman, 2005). For example, during migraine attacks there is a marked increase in the plasma levels of CGRP and the administration of a recently developed CGRP blocker, BIBN4096BS, causes the headache to subside and the neuropeptide levels to normalize (Olesen et al., 2004). On the other hand, the efficacy of SER agonists for migraine therapy is known, and this amine, probably along with CGRP, has been hypothesized to be involved in trigeminal pain (Moskowitz et al., 1979) by activating 5- HT1B, 5-HT1D (Bonaventure et al., 1998; Wotherspoon & Priestly, 2000) and 5-HT7 (Terrón et al., 2001; see also Classey et al., 2010) receptors. Indeed, the systemic administration of sumatriptan, the most-studied of the serotonergic drugs now collectively known as the triptans, lowers CGRP levels to nearly normal levels coincident with headache relief (Goadsby & Edvinsson, 1991). NO, an inflammatory mediator, is also currently thought of as a key molecule in migraine pain, possibly in concert with CGRP (Thomsen & Olesen, 1996). Results from animal studies have provided evidence for the involvement of NO in sensitation and/or activation of the trigeminovascular system and repressed release of CGRP from trigeminal neurons in response to treatment with NO donors or application of the anti-migraine drug sumatriptan, which has affinity for 5-HT1B, 5-HT1D and 5-HT1F receptors (Bellamy et al., 2006). It seems likely that NO production and neuropeptide release are functionally linked in severe vascular headaches. Conversely, SP, which along with CGRP is the most definitely characterized peptide in the TG, is not released in the cranial blood flow in migraine suggesting that SP does not take part in vascular nociception in man

neurotoxicity. Alternatively, it is reasonable to speculate that the possible endogenous production of NO might underlie a defense mechanism of the neurons against nerve injury

In summary, these findings provide compelling evidence that the content of the neurochemicals in both central and peripheral trigeminal primary afferent neurons is not static and their level may vary in case of marked changes in the environmental conditions,

Trigeminal primary afferent neurons have been the focus of intense research also because of their contribution to acute and chronic pain states, and the important role played by trigeminal nociceptive pathways in most clinically significant pain disorders. In response to trigeminal nerve activation, craniofacial pain symptoms can manifest as transient pain conditions as reported with toothaches and headaches, or can transform into more chronic pain conditions such as migraine, temporomandibular joint disorders or trigeminal neuralgia (Durham & Garrett, 2010). Apart from electrical activation, chemical activation of the trigeminal nerve leads to an afferent and efferent release of certain neuropeptides that facilitate peripheral inflammatory responses and causes activation of second-order neurons involved in pain transmission (Buzzi, 2001). Accumulating evidence suggests that CGRP and NO are involved in the underlying pathophysiology of all vascular headaches, the vast majority of which are associated with an inflammatory process. In particular, CGRP, a potent vasodilator and pro-inflammatory agent which is expressed by trigeminal nociceptors, has been identified as a key player in the pathomechanism of migraine headache (McCulloch et al., 1986). Clinical studies have also shown a clear association between the head pain and the release of CGRP, from the trigeminovascular system (for a review, see Edvinsson & Uddman, 2005). For example, during migraine attacks there is a marked increase in the plasma levels of CGRP and the administration of a recently developed CGRP blocker, BIBN4096BS, causes the headache to subside and the neuropeptide levels to normalize (Olesen et al., 2004). On the other hand, the efficacy of SER agonists for migraine therapy is known, and this amine, probably along with CGRP, has been hypothesized to be involved in trigeminal pain (Moskowitz et al., 1979) by activating 5- HT1B, 5-HT1D (Bonaventure et al., 1998; Wotherspoon & Priestly, 2000) and 5-HT7 (Terrón et al., 2001; see also Classey et al., 2010) receptors. Indeed, the systemic administration of sumatriptan, the most-studied of the serotonergic drugs now collectively known as the triptans, lowers CGRP levels to nearly normal levels coincident with headache relief (Goadsby & Edvinsson, 1991). NO, an inflammatory mediator, is also currently thought of as a key molecule in migraine pain, possibly in concert with CGRP (Thomsen & Olesen, 1996). Results from animal studies have provided evidence for the involvement of NO in sensitation and/or activation of the trigeminovascular system and repressed release of CGRP from trigeminal neurons in response to treatment with NO donors or application of the anti-migraine drug sumatriptan, which has affinity for 5-HT1B, 5-HT1D and 5-HT1F receptors (Bellamy et al., 2006). It seems likely that NO production and neuropeptide release are functionally linked in severe vascular headaches. Conversely, SP, which along with CGRP is the most definitely characterized peptide in the TG, is not released in the cranial blood flow in migraine suggesting that SP does not take part in vascular nociception in man

and, thus, improve survival and active regeneration of MTN neurons.

thus implying neuroplasticity as another major attribute of theirs.

**5. Clinical relevance** 

(Holthusen et al., 1997). It has recently been demonstrated that SP release in the TG is predominantly increased after orofacial inflammation (Neubert et al. 2000) and such a release may play an important role in determining the trigeminal inflammatory alloying concerning the temporomandibular joint disorder (Takeda et al., 2005). The authors point out that NK1 receptor antagonists may be useful as therapeutic agents to prevent the mechanical allodynia. P2X3 receptors may be another therapeutic target for treating temporomandibular joint disorder pain (Shinoda et al., 2005).

Another common clinical concern regarding the trigeminal nerve is trigeminal neuralgia. Evidence for the role of SP and CGRP in trigeminal neuralgia pain is clearly apparent (Stoyanova & Lazarov, 2001). Inhibitory neurotransmitters, such as GABA, are thought to have a role in analgesia and many GABAergic drugs, acting through metabotropic GABAB receptors, are useful in the treatment of migraine and trigeminal neuralgia. With regard to the latter, a GABA analogue, gabapentin, has been reported to be effective in the management of migraine and trigeminal neuralgia, and also displays anti-nociceptive activity in various animal pain models. In addition, a selective GABAB receptor agonist, baclofen, has been shown to elicit pain relief and, thus, it might play a therapeutic role in the inhibition of nociceptive hypersensitivity in trigeminal neuralgia (Fromm, 1994).

Clinically relevant is also pain, caused by a central or peripheral nerve lesion which is commonly termed neuropathic pain, and the concomitant neurogenic inflammation. Orofacial neuropathic pain, like anywhere in the body, may occur as a result of tissue damage and the activation of nociceptors, which transmit a noxious stimulus to the brain (Vickers & Cousins, 2000). The abnormal facial pain involves regeneration of damaged nerve fibers and may account for chemical changes in injured neuronal cell bodies. As mentioned above, a variety of neuropeptides, such as SP, CGRP, GAL and NPY, are upregulated following peripheral axotomy (see Table 2) and craniofacial muscle inflammation (Ambalavanar et al., 2006). Results from studies on animal pain models have suggested that NPY and its receptors are potential targets for treatment of pain, especially neuropathic pain (Silva et al., 2002). The efficacy of opioid receptor agonists in modulation of nociceptive inputs in a wide range of orofacial pain models, including neuropathic pain (Catheline et al., 1998) and inflammatory pain (Ko et al., 1998) is also acknowledged. Given that NGF is responsible for the increased expression of SP and CGRP during neurogenic inflammation (Lundy & Linden, 2004), it is not much surprising that the systemic administration of anti-NGF neutralizing antibodies prevents the up-regulation of neuropeptides in primary afferent neurons innervating the inflamed skin (Woolf et al., 1994). Changes in the injured neurons can also influence the ability of the surrounding glial cells to release neuromodulators such as NO and ATP, thus implicating satellite glial cells in the TG as a determinant of orofacial neuropathic pain. This fits well with the notion that the P2X3 receptor is transiently up-regulated and anterogradely transported in trigeminal primary afferent neurons after neuropathic injury (Eriksson et al., 1998). Purinergic receptors on TG neurons are thus likely to be a legitimate target for therapeutic intervention in neuropathic pain and orofacial inflammation (Ambalavanar et al., 2005). Recent findings further demonstrate that masseter inflammation differentially modulates Glu receptor subunits and that the induced changes in them may contribute to functionally different aspects of craniofacial muscle pain processing under inflammatory conditions (Lee and Ro, 2007).

The Neurochemical Anatomy of Trigeminal Primary Afferent Neurons 185

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#### **6. Concluding remarks**

Based on the information now available, it has become evident that miscellaneous transmitter candidates are associated with a subset of trigeminal primary afferent neurons and, besides, these are well-innervated by aminergic, peptidergic and nitrergic fibers of a probable extrinsic origin. The data also suggest that some classical neurotransmitters and neuropeptides not only mediate trans-synaptic information coding but can also act as longterm morphogenetic signals and trophic factors. Progressive discovery of the multiplicity of chemical messengers, of coexistent transmitters (or transmitter candidates), their receptors and transducing mechanisms, and of local mechanisms for transmitter release, has reinforced the view that chemical coding in trigeminal primary afferent neurons, either peripherally or centrally, is multiple, heterogeneous, plastically varying and characterized by a wide spectrum of co-existing messenger substances. In line with similar morphological features and trophic factor requirements, as well as diverse central and peripheral targets, and physiological properties, we show that TG and MTN neurons have both similarities and differences in their neurochemical content. On the one hand, the most important similarity relates to the fact that both central and peripheral trigeminal primary afferent neurons express, indeed to a varying degree, classical transmitters and neuronal markers, such as calcium-binding proteins. On the other hand, the most marked spatial difference is the presence of certain neuropeptides in the TG cell bodies and their absence in the MTN neuronal somata under normal conditions. As argued before, we believe that the differently fated embryonic migration, synaptogenesis, and peripheral and central target field innervation can possibly affect the individual neurochemical phenotypes of trigeminal primary afferent neurons.

#### **7. Acknowledgments**

I am grateful to all members of my laboratory for their generous help and to many colleagues whose constructive suggestions enriched this chapter. I would also like to thank Dr. Angel Dandov for critical reading and editing of the manuscript.

#### **8. References**


Based on the information now available, it has become evident that miscellaneous transmitter candidates are associated with a subset of trigeminal primary afferent neurons and, besides, these are well-innervated by aminergic, peptidergic and nitrergic fibers of a probable extrinsic origin. The data also suggest that some classical neurotransmitters and neuropeptides not only mediate trans-synaptic information coding but can also act as longterm morphogenetic signals and trophic factors. Progressive discovery of the multiplicity of chemical messengers, of coexistent transmitters (or transmitter candidates), their receptors and transducing mechanisms, and of local mechanisms for transmitter release, has reinforced the view that chemical coding in trigeminal primary afferent neurons, either peripherally or centrally, is multiple, heterogeneous, plastically varying and characterized by a wide spectrum of co-existing messenger substances. In line with similar morphological features and trophic factor requirements, as well as diverse central and peripheral targets, and physiological properties, we show that TG and MTN neurons have both similarities and differences in their neurochemical content. On the one hand, the most important similarity relates to the fact that both central and peripheral trigeminal primary afferent neurons express, indeed to a varying degree, classical transmitters and neuronal markers, such as calcium-binding proteins. On the other hand, the most marked spatial difference is the presence of certain neuropeptides in the TG cell bodies and their absence in the MTN neuronal somata under normal conditions. As argued before, we believe that the differently fated embryonic migration, synaptogenesis, and peripheral and central target field innervation can possibly affect the individual neurochemical phenotypes of trigeminal

I am grateful to all members of my laboratory for their generous help and to many colleagues whose constructive suggestions enriched this chapter. I would also like to thank

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**6. Concluding remarks** 

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**9** 

**β-Endorphin and Alcoholism** 

*2Neuroscience Program, Department of Psychology,* 

Extensive research over several decades indicates a strong relationship between alcohol use disorders and anxiety. Stress and anxiety are implicated in both the initiation of alcohol consumption and the maintenance of heavy drinking (Kushner et al., 1990; Pohorecky, 1981). For instance, anxiety disorders reliably precede the onset of alcoholism (Hettema et al., 2003) and over 35% of patients diagnosed with generalized anxiety disorder have engaged in self-medication with alcohol, defined as "drinking more than usual" in response to a stressor (Bolton et al., 2006). Stressors have also been linked to relapse in abstinent adults (Adinoff et al., 2005; Brown et al., 1995). Moreover, there is strong support suggesting that stress and alcohol abuse co-present so frequently as a result of common genetic factors in stress response systems. Genetically inherited variations in the hypothalamic-pituitaryadrenal (HPA) axis have been implicated in vulnerability to initial alcohol abuse, sustained alcohol addiction, and relapse (Crabbe et al., 2006; Kreek & Koob, 1998; Shaham et al., 2003). This paper will discuss the putative contribution of b-endorphin to the negatively

**2. The hypothalamo-pituitary-adrenocortical axis and -endorphin** 

loop, inhibiting further CRH and ACTH synthesis in the brain.

Although a thorough understanding of this nebulous concept is lacking, stress has been operationally defined as activation of the hypothalamo-pituitary-adrenocortical (HPA) axis in response to both physical and psychological stressors (for example, Pacak and Palkovits, 2001; Uhart and Wand 2009). The stress response is coordinated by neuronal activation of the paraventricular nucleus in the hypothalamus leading to the release of corticotrophinreleasing hormone (CRH) into the hypothalamic-hypophyseal portal. CRH reaches receptors on the anterior pituitary and initiates the synthesis of ACTH from its precursor, proopiomelanocortin (POMC). ACTH is released into the bloodstream where it influences the adrenal glands, initiating production and release of cortisol into the blood (corticosterone in rodents). Cortisol plays a fundamental role in the systemic reaction that characterizes physiological stress, though high levels of cortisol act in a negative feedback

**1. Introduction** 

reinforcing effects of alcohol.

Sarah M. Barry1 and Judith E. Grisel2

*The Medical University of South Carolina,* 

*1Department of Neurosciences,* 

*Furman University, Greenville, SC,* 

*Charleston, SC,* 

*USA* 

