**3.1. Receptor antagonist antiemetic regimens such as netupitant/palonosetron (NEPA)**

The ultimate aim of prophylactic management of chemotherapy-induced nausea and vomiting is to abolish both the acute- and delayed phases of vomiting which will help to improve the well-being and quality of life of cancer patients receiving chemotherapy. Cisplatin-like chemotherapeutics cause release of multiple emetogenic neurotransmitters in both the central nervous system and the gastrointestinal tract and no available single antiemetic administered alone can provide complete efficacy. Significant initial work had suggested that while activation of 5-HT<sup>3</sup> Rs by serotonin in the gastrointestinal tract is involved in the mediation of acute phase of chemotherapy-induced nausea and vomiting, the delayed phase is due to stimulation of NK1 Rs subsequent to release of substance P in the brainstem [77, 78]. However, our more recent findings suggest that 5-HT and substance P are concomitantly involved in both emetic phases in the gastrointestinal tract as well as in the brainstem [2, 16]. While netupitant is a highly selective and a longer-acting second generation NK<sup>1</sup> R antagonist, palonosetron is considered as a second generation 5-HT<sup>3</sup> R antagonist with a unique antiemetic profile in both humans [79, 80] and the least shrew model of emesis [45]. A successful regimen of an oral fixed combined dose of netupitant/palonosetron (NEPA) (**Figure 2**) has been formulated with over 85% clinical efficacy, good tolerability, and high central nervous system penetrance for the prophylactic treatment of acute and delayed chemotherapy-induced nausea and vomiting in cancer patients receiving chemotherapy [9, 81, 82].

Recent evidence accumulated from HEK293 cells stably transfected with 5-HT<sup>3</sup> Rs suggest that suppression of Ca2+ signaling is involved in antiemetic efficacy of both palonosetron and netupitant. Indeed, Rojas et al. [83, 84] have shown that palonosetron causes a persistent inhibition of 5-HT<sup>3</sup> R function as reflected by a near complete suppression of 5-HT-evoked extracellular Ca2+ influx. They have further demonstrated that palonosetron can prevent enhancement of substance P-induced intracellular Ca2+ release in response to serotonin in NG108–15 cells expressing both 5-HT<sup>3</sup> Rs and NK1 Rs [85]. Our Ca2+ monitoring studies performed on acutelyprepared least shrew brainstem slices also demonstrate that palonosetron can abolish enhancement of intracellular Ca2+ levels in brainstem slices evoked by the selective 5-HT<sup>3</sup> R agonist 2-Methyl-5-HT [25]. The latter finding provides more relevant ex-vivo evidence for the Ca2+ modulating antiemetic effect of palonosetron in a vomit-competent species. The role of netupitant in suppression of substance P-evoked enhancement of intracellular Ca2+ levels has also been demonstrated via Ca2+ mobilization assays in vitro in CHO cells expressing the human NK1 Rs. Moreover, pronetupitant, an intravenous alternative to the oral netupitant, appears to be more potent than netupitant in both in vitro Ca2+ measurement studies and in vivo animal behavioral evaluations of substance P in rats [86]. In addition, another clinically approved NK<sup>1</sup> R antagonist antiemetic rolapitant, has been shown to suppress the ability of the selective NK<sup>1</sup> R agonist GR73632 to evoke intracellular Ca2+ release [9, 87–89]. The discussed findings clearly suggest that Ca2+ is a major player in the initiation of vomiting evoked by diverse emetogens.

#### **3.2. Cannabinoid CB1 receptor agonists**

counter-balance the cytosolic intracellular Ca2+ release from the sarco/endoplasmic reticulum

(RyRs) [49–51]. Thapsigargin also causes intracellular release of stored Ca2+ from the sarco/ endoplasmic reticulum into the cytosol which subsequently evokes extracellular Ca2+ influx predominantly through store-operated Ca2+ entry (SOCE) in non-excitable cells [52–54]. In total, these events lead to a significant rise in the free concentration of cytosolic Ca2+ [55–57]. In addition, a partial involvement of LTCCs in thapsigargin-evoked contraction has also been demonstrated in rat stomach smooth muscle cells [58], rat gastric smooth muscle [59], and cat gastric smooth muscle [60]. On the other hand, the potential of thapsigargin as a Ca2+ modulating cancer chemotherapeutic agent has been evaluated in both cells and animal models [61]. Thapsigargin-evoked increases in cytosolic Ca2+ concentration can lead to cell apoptosis, which can result in eradication of cancer cells of the breast [62], prostate [63], colon [64] and kidneys [65]. Clinically, a prodrug form of thapsigargin, mipsagargin, is currently under clinical trial as a targeted cancer chemotherapeutic agent with selective toxicity against cancer cells in tumor sites with minimal side-effects to the host [66–69]. In our studies, intraperitoneal administration of thapsigargin (0.1–10 mg/kg) caused vomiting in least shrews in a dose-dependent, but bell-shaped manner, with maximal efficacy at 0.5 mg/kg. An important consideration for the emetic potential of thapsigargin is that it augments the cytosolic levels of free Ca2+ in emetic loci as a result of SERCA inhibition as indicated in our latest discussed finding [70], which is the first study to reflect emesis as a major side-effect of thapsigargin when delivered systemically. c-Fos induction has been used to evaluate differential neuronal activation [71]. Our lab has applied immunostaining and detected c-Fos induction in the brainstem emetic nuclei to demonstrate central responsiveness to peripheral administration of a variety of emetogens [4, 70, 72, 73]. The participation of the central emetic neurons in FPL64176-induced vomiting is further indicated by evoked c-Fos expression in brainstem emetic nuclei, the nucleus tractus solitarius and the dorsal motor nucleus of the vagus (unpublished data). Thus, the bloodbrain barrier permeable agent FPL64176 [74–76] could excite emetic neurons directly in the nucleus tractus solitarius and the dorsal motor nucleus of the vagus. Thapsigargin (0.5 mg/kg) also causes increases in c-Fos immunoreactivity in the brainstem emetic nuclei including the area postrema, the nucleus tractus solitarius and the dorsal motor nucleus of the vagus [70].

**3. Ca2+ intervention mechanisms relevant to antiemetic approaches**

The ultimate aim of prophylactic management of chemotherapy-induced nausea and vomiting is to abolish both the acute- and delayed phases of vomiting which will help to improve the well-being and quality of life of cancer patients receiving chemotherapy. Cisplatin-like chemotherapeutics cause release of multiple emetogenic neurotransmitters in both the central nervous system and the gastrointestinal tract and no available single antiemetic administered alone can provide complete efficacy. Significant initial work had suggested that while activa-

phase of chemotherapy-induced nausea and vomiting, the delayed phase is due to stimulation

Rs by serotonin in the gastrointestinal tract is involved in the mediation of acute

**3.1. Receptor antagonist antiemetic regimens such as netupitant/palonosetron** 

**(NEPA)**

tion of 5-HT<sup>3</sup>

Rs) and ryanodine receptors

into the cytoplasm via the inositol trisphosphate receptors (IP<sup>3</sup>

114 Calcium and Signal Transduction

Before the introduction of first generation 5-HT<sup>3</sup> R antagonists, several phyto- and synthetic cannabinoids including dronabinol (delta-9-tetrahydrocannabinol, Δ<sup>9</sup> -THC (**Figure 2**)), levonantradol and nabilone, were evaluated in cancer patients for suppression of chemotherapy-induced nausea and vomiting that were not effectively controlled by other available antiemetics [2, 90]. Cannabinoids are increasingly being tested as antiemetics against cisplatin-induced emesis in animal experiments using house musk shrews [91], ferrets [92], or least shrews [73, 93]; nausea-related behavior in rats [91]; radiation-induced emesis in the least shrew [94]; as well as both phases of chemotherapy-induced nausea and vomiting in the clinic [95–97]. Cannabinoid agonists exert their antiemetic efficacy via direct activation of CB<sup>1</sup> receptors (CB1 R) since their antiemetic effects were reversed by CB<sup>1</sup> R antagonists [92, 94, 98–100]. Significant evidence for a role for CB<sup>2</sup> Rs in emesis is currently lacking [101]. The presence of CB1 Rs in the brainstem nuclei involved in emesis has been confirmed, with a high density of CB1 R immunoreactivity in the dorsal motor nucleus of the vagus and the medial subnucleus

vagal complex inhibits synaptic transmission to the dorsal motor nucleus of the vagus neurons, which may explain suppression of visceral motor responses caused by cannabinoids.

dependent neurotransmitter release from presynaptic nerve terminals which consequently leads to inhibition of neurotransmission [108]. In chemotherapy-induced nausea and vomiting,

Indeed, the adenylyl cyclase/cyclic AMP (cAMP)/protein kinase A (PKA) signal transduction system is a well-established emetic signaling pathway [109]. PKA activation is known to phosphorylate both Ca2+ ion channels on plasma membrane and intracellular endoplasmic IP<sup>3</sup>

which respectively increase extracellular Ca2+ influx and internal Ca2+ release from the sarco/

which mediates inhibition of adenylate cyclase. This inhibition has been proposed to be the fun-

which would ultimately reduce postsynaptic neuronal activation in both dorsal vagal complex and gastrointestinal tract [93, 103]. Moreover, dose-dependent inhibitory action of cannabinoid

multiple experimental systems [111–115]. Additionally, cannabinoid CB<sup>1</sup>

R agonists on extracellular Ca2+ influx via a number of voltage-gated Ca2+ channels residing in the cell membrane including N-type, P/Q type and L-type have been demonstrated in

Rs in a non-competitive manner and thus prevent extracellular Ca2+ influx [115, 116].

on the sarco/endoplasmic reticulum membrane, RyRs. Ca2+-induced Ca2+ release is a wellestablished feature of Ca2+ signal amplification. During neuronal activation, Ca2+-induced Ca2+ release Ca2+ signaling involves increased concentration of cytoplasmic Ca2+ via extracellular Ca2+ influx through voltage-gated Ca2+ channels (e.g., LTCCs) present on the cell membrane, which then causes release of stored intracellular Ca2+ from the sarco/endoplasmic reticulum into the cytosol through RyRs [117]. In fact RyRs have a wide distribution in the central nervous system including the brainstem [118]. RyRs not only can regulate Ca2+ homeostasis, but also other critical brain functions including neurotransmitter release [117]. Increased serum levels of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α), is associated with chemotherapy-evoked vomiting [119]. TNF-α can excite vagal afferent terminals by augmenting Ca2+ release from sarco/endoplasmic reticulum stores via sensitization of RyRs which

subsequently amplifies neurotransmission in the brainstem [15]. Cannabinoid CB<sup>1</sup>

ing the broad-spectrum antiemetic efficacy of CB<sup>1</sup>

prevent the TNF-α-evoked sensitization of RyRs and therefore attenuate intracellular Ca2+ release from the sarco/endoplasmic reticulum stores [15]. Peripheral RyRs also play a critical role in agonist-evoked Ca2+ oscillations in gut epithelial cells [120]. Therefore, the ability of

R agonists in preventing both extracellular Ca2+ influx as well as intracellular Ca2+ release from the sarco/endoplasmic reticulum stores may be the fundamental mechanisms underly-

Glucocorticoids, used primarily as anti-allergic and anti-inflammatory drugs. They are also effective, either alone or in combination with other antiemetics, for the suppression of nausea

R cannabinoid agonists.

R-mediated antiemetic action of cannabinoids appears to be directly related to presynaptic inhibition of release of emetic neurotransmitters from nerve terminals. **Figure 4** may

R stimulation can result in inhibition of Ca2+-

Rs are known to be Gi/o-protein coupled receptors

R agonists attenuating Ca2+-dependent emetic neurotransmitter release

R agonists appear to inhibit the intracellular Ca2+ release channels located

R agonists from the Ca2+ perspective.

http://dx.doi.org/10.5772/intechopen.78370

Role of Calcium in Vomiting

Rs,

117

R agonists also block

R agonists

Furthermore, in the central nervous system CB<sup>1</sup>

endoplasmic reticulum stores [110]. CB<sup>1</sup>

damental reason for CB1

help to explain the antiemetic action of cannabinoid CB<sup>1</sup>

the CB1

CB1

5-HT<sup>3</sup>

CB1

**3.3. Glucocorticoids**

Furthermore, CB<sup>1</sup>

**Figure 4.** A schematic explanation of the antiemetic action of cannabinoid CB<sup>1</sup> R agonists from the perspective of Ca2+ signaling. Activation of CB<sup>1</sup> R initiates a Gi/o mechanism leading to the downregulation of extracellular Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) as well as endoplasmic reticulum (ER) Ca2+ release via ryanodine receptors (RyRs) which has the potential to be activated by extracellular Ca2+ entry through VGCCs. The reduction in cytosolic Ca2+ attenuates Ca2+-dependent emetic neurotransmitter release, which further results in a reduction in postsynaptic neuronal activation, and ultimately suppression of the vomiting behavior [93, 103, 117].

of the nucleus tractus solitarius, a moderate density in the commissural subnucleus of the nucleus tractus solitarius, and lower densities in the area postrema and dorsal subnucleus of the nucleus tractus solitarius [73, 92]. CB<sup>1</sup> R distribution has been also observed in the myenteric plexus of the stomach and duodenum [92]. Furthermore, CB<sup>1</sup> Rs have been localized in the myenteric plexus of the rat and guinea pig intestine in nearly all cholinergic neuron terminals [102, 103]. These as well as behavioral evidence [42] suggest that the antiemetic action of cannabinoids involve both the central dorsal vagal complex and intestinal emetic loci. In addition, primary cultures of guinea-pig myenteric neurons express CB<sup>1</sup> Rs and exogenously added cannabinoids suppress their neuronal activity, synaptic transmission and mitochondrial transport along axons [104]. Moreover, the CB1/2R agonist WIN55212-2 can suppress intestinal activity since it can attenuate the electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation of the guinea-pig small intestine in a Ca2+-dependent and CB1 R-specific manner [105]. Thus, CB<sup>1</sup> R agonists in the in vivo setting can also suppress the gastrointestinal tract motility [104]. Using whole-cell patch-clamp recordings in brainstem slices, Derbenev et al. [106, 107] have shown that activation of presynaptic CB<sup>1</sup> Rs in the dorsal vagal complex inhibits synaptic transmission to the dorsal motor nucleus of the vagus neurons, which may explain suppression of visceral motor responses caused by cannabinoids.

Furthermore, in the central nervous system CB<sup>1</sup> R stimulation can result in inhibition of Ca2+ dependent neurotransmitter release from presynaptic nerve terminals which consequently leads to inhibition of neurotransmission [108]. In chemotherapy-induced nausea and vomiting, the CB1 R-mediated antiemetic action of cannabinoids appears to be directly related to presynaptic inhibition of release of emetic neurotransmitters from nerve terminals. **Figure 4** may help to explain the antiemetic action of cannabinoid CB<sup>1</sup> R agonists from the Ca2+ perspective. Indeed, the adenylyl cyclase/cyclic AMP (cAMP)/protein kinase A (PKA) signal transduction system is a well-established emetic signaling pathway [109]. PKA activation is known to phosphorylate both Ca2+ ion channels on plasma membrane and intracellular endoplasmic IP<sup>3</sup> Rs, which respectively increase extracellular Ca2+ influx and internal Ca2+ release from the sarco/ endoplasmic reticulum stores [110]. CB<sup>1</sup> Rs are known to be Gi/o-protein coupled receptors which mediates inhibition of adenylate cyclase. This inhibition has been proposed to be the fundamental reason for CB1 R agonists attenuating Ca2+-dependent emetic neurotransmitter release which would ultimately reduce postsynaptic neuronal activation in both dorsal vagal complex and gastrointestinal tract [93, 103]. Moreover, dose-dependent inhibitory action of cannabinoid CB1 R agonists on extracellular Ca2+ influx via a number of voltage-gated Ca2+ channels residing in the cell membrane including N-type, P/Q type and L-type have been demonstrated in multiple experimental systems [111–115]. Additionally, cannabinoid CB<sup>1</sup> R agonists also block 5-HT<sup>3</sup> Rs in a non-competitive manner and thus prevent extracellular Ca2+ influx [115, 116].

Furthermore, CB<sup>1</sup> R agonists appear to inhibit the intracellular Ca2+ release channels located on the sarco/endoplasmic reticulum membrane, RyRs. Ca2+-induced Ca2+ release is a wellestablished feature of Ca2+ signal amplification. During neuronal activation, Ca2+-induced Ca2+ release Ca2+ signaling involves increased concentration of cytoplasmic Ca2+ via extracellular Ca2+ influx through voltage-gated Ca2+ channels (e.g., LTCCs) present on the cell membrane, which then causes release of stored intracellular Ca2+ from the sarco/endoplasmic reticulum into the cytosol through RyRs [117]. In fact RyRs have a wide distribution in the central nervous system including the brainstem [118]. RyRs not only can regulate Ca2+ homeostasis, but also other critical brain functions including neurotransmitter release [117]. Increased serum levels of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α), is associated with chemotherapy-evoked vomiting [119]. TNF-α can excite vagal afferent terminals by augmenting Ca2+ release from sarco/endoplasmic reticulum stores via sensitization of RyRs which subsequently amplifies neurotransmission in the brainstem [15]. Cannabinoid CB<sup>1</sup> R agonists prevent the TNF-α-evoked sensitization of RyRs and therefore attenuate intracellular Ca2+ release from the sarco/endoplasmic reticulum stores [15]. Peripheral RyRs also play a critical role in agonist-evoked Ca2+ oscillations in gut epithelial cells [120]. Therefore, the ability of CB1 R agonists in preventing both extracellular Ca2+ influx as well as intracellular Ca2+ release from the sarco/endoplasmic reticulum stores may be the fundamental mechanisms underlying the broad-spectrum antiemetic efficacy of CB<sup>1</sup> R cannabinoid agonists.

#### **3.3. Glucocorticoids**

of the nucleus tractus solitarius, a moderate density in the commissural subnucleus of the nucleus tractus solitarius, and lower densities in the area postrema and dorsal subnucleus of

voltage-gated Ca2+ channels (VGCCs) as well as endoplasmic reticulum (ER) Ca2+ release via ryanodine receptors (RyRs) which has the potential to be activated by extracellular Ca2+ entry through VGCCs. The reduction in cytosolic Ca2+ attenuates Ca2+-dependent emetic neurotransmitter release, which further results in a reduction in postsynaptic neuronal

R initiates a Gi/o mechanism leading to the downregulation of extracellular Ca2+ influx through

the myenteric plexus of the rat and guinea pig intestine in nearly all cholinergic neuron terminals [102, 103]. These as well as behavioral evidence [42] suggest that the antiemetic action of cannabinoids involve both the central dorsal vagal complex and intestinal emetic loci. In

added cannabinoids suppress their neuronal activity, synaptic transmission and mitochondrial transport along axons [104]. Moreover, the CB1/2R agonist WIN55212-2 can suppress intestinal activity since it can attenuate the electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation of the guinea-pig small intestine in a Ca2+-dependent

the gastrointestinal tract motility [104]. Using whole-cell patch-clamp recordings in brainstem

R distribution has been also observed in the myen-

R agonists in the in vivo setting can also suppress

Rs have been localized in

R agonists from the perspective of Ca2+

Rs and exogenously

Rs in the dorsal

the nucleus tractus solitarius [73, 92]. CB<sup>1</sup>

signaling. Activation of CB<sup>1</sup>

116 Calcium and Signal Transduction

R-specific manner [105]. Thus, CB<sup>1</sup>

and CB1

teric plexus of the stomach and duodenum [92]. Furthermore, CB<sup>1</sup>

**Figure 4.** A schematic explanation of the antiemetic action of cannabinoid CB<sup>1</sup>

activation, and ultimately suppression of the vomiting behavior [93, 103, 117].

addition, primary cultures of guinea-pig myenteric neurons express CB<sup>1</sup>

slices, Derbenev et al. [106, 107] have shown that activation of presynaptic CB<sup>1</sup>

Glucocorticoids, used primarily as anti-allergic and anti-inflammatory drugs. They are also effective, either alone or in combination with other antiemetics, for the suppression of nausea and vomiting. Indeed, dexamethasone (**Figure 2**), one of the clinically used glucocorticoids, is effective in reducing both acute and delayed chemotherapy-induced nausea and vomiting, and when combined with 5-HT<sup>3</sup> or neurokinin NK1 antagonists, it is utilized in patients receiving high emetogenic chemotherapy [6]. Glucocorticoids' antiemetic effect has been related to its inhibitory effects in the following facets: (i) glucocorticoids control the inflammatory response involved in mediating chemotherapy-induced nausea and vomiting by reducing the production of inflammatory mediators such as cytokines, chemokines, inducible nitric oxide synthase, and increasing the gene transcription of anti-inflammatory proteins [6]; (ii) glucocorticoids can inhibit 5-HT and substance P release, both of which can evoke emesis [6, 121], (iii) glucocorticoids can cross the blood-brain barrier and can exert direct central inhibitory effects on the nucleus tractus solitarius [6], which may be due to a decrease in abnormal elevation of cytosolic Ca2+ concentration as well as downstream Ca2+ signals and the maintenance of Ca2+ homeostasis within the cell [122], (iv) inhibitory actions of glucocorticoid could also be due to increased release of endocannabinoids, anandamide and 2-arachidonoylglycerol, evoked by glucocorticoid administration which will then be followed by subsequent CB<sup>1</sup> R activation as well as glucocorticoid facilitation of synaptic γ-aminobutyric acid (GABA) release and suppression of glutamate release [123, 124]. The endocannabinoid system is composed of CBRs, endocannabinoids and the enzymes involved in their synthesis. Anandamide and 2-arachidonoylglycerol are among the well-studied endocannabinoids and endogenous activators of CBRs [125]. The role of CB1 R agonists as antiemetics was discussed in Section 2.2. It has been suggested that dexamethasone may decrease motion sickness through modulation of the endocannabinoid/ CB1 receptor system on the terminals of the nucleus tractus solitarius neurons that project to the output neurons of the DMNV as well as by endocannabinoid/CB<sup>1</sup> receptor system-mediated inhibition of transmitter release from interneurons of the nucleus tractus solitarius [99, 126]. Selective elevation of 2-arachidonoylglycerol by inhibition of its major metabolic enzyme monoacylglycerol lipase, have been shown to suppress lithium chloride evoked vomiting in the house musk shrew (*Suncus murinus*) [127]. However, intraperitoneal administration of the endocannabinoid 2-arachidonoylglycerol can evoke vomiting in the least shrew in a dose-dependent manner probably via its rapid metabolism to arachidonic acid which is also a potent emetogen in this species [128]. Moreover, the cancer chemotherapeutic agent cisplatin can increase 2-arachidonoylglycerol but not anandamide levels in the least shrew brain [129].

including FPL 64176 (10 mg/kg, i.p.), the peripherally-acting and non-selective 5-HT<sup>3</sup>

behavior was recorded for 30 min. Our results suggest that both amlodipine and nifedipine act by suppressing the influx of extracellular Ca2+, thereby delay the onset as well as protecting least shrews from vomiting, further supporting our proposed Ca2+ hypothesis of emesis. Nifedipine appears to be more potent than amlodipine against vomiting caused by FPL64176, 5-HT, 2-Methyl-5-HT, GR73632, quinpirole and McN-A343. These potency disparities could be explained in terms of their pharmacokinetic and pharmacodynamic differences [130–139].

Unlike the above tested emetogens which can evoke vomiting within minutes of administration, cisplatin (10 mg, i.p.) requires more exposure time (30–45 min) to begin to induce emesis since only its metabolites are emetogenic. The relative efficacy of amlodipine (5 mg/kg., i.p.) in reducing the frequency of cisplatin-evoked early vomiting by 80% compared with the observed lack of antiemetic action of nifedipine up to 20 mg/kg [45, 46], could be explained in terms of positively charged amlodipine associating more slowly with LTCCs, requiring more exposure time not only to reach its sites of action, but also to compensate for its slower receptor binding kinetics, which can lead to a more gradual onset of antagonism [140]. In addition, intracerebroventricular microinjection of another LTCC antagonist, nitrendipine, has been shown to attenuate nicotine-induced vomiting in the cat [141], which further supports the discussed broad-spectrum antiemetic efficacy of nifedipine and amlodipine as observed in the least shrew model. Cisplatin-based chemotherapeutics induce both immediate and delayed vomiting in humans and in vomit-competent animals [16, 142, 143]. In the least shrew, cisplatin (10 mg/kg, i.p.) causes emesis over 40 h with respective peak early- and delayed-phases occurring at 1–2 and 32–34 h post-injection [144]. Amlodipine, due to its unique pharmacokinetics, may offer practical advantages over other calcium antagonists in cisplatin-evoked delayed emesis.

In 1996 Hargreaves and co-workers [20] demonstrated that members of all three major

1-(m-chlorophenyl)-biguanide to increase intracellular Ca2+ concentration in cell lines that possess either one or both of these two different Ca2+-ion channels. The latter interaction is not competitive since the binding site for the different classes of LTCC antagonists appear

[145, 146]. These findings provide possible mechanisms via which antagonists of both LTCCs

ing selective agonists, including the vomiting behavior induced by their corresponding selective agonists FPL64176 and 2-Methyl-5-HT as we reported previously [45]. We have further demonstrated that when non-effective antiemetic doses of their selective antagonists (nifedipine

Rs can mutually prevent the biochemical and behavioral effects of their correspond-

nist 5-HT (5 mg/kg, i.p.), the peripherally/centrally-acting and more selective 5-HT<sup>3</sup>

2-Methyl-5-HT (5 mg/kg, i.p.), the dopamine D<sup>2</sup>

(2 mg/kg, i.p.), and the selective neurokinin NK<sup>1</sup>

**4.2. Potentiation of antiemetic efficacy of 5-HT<sup>3</sup>**

not to be the same as the serotonin 5-HT<sup>3</sup>

instead, is an allosteric site in the 5-HT<sup>3</sup>

classes of LTCC antagonists can prevent the ability of the 5-HT<sup>3</sup>

from enterochromaffin cells can be prevented by antagonists of both 5-HT<sup>3</sup>

**LTCC blockers**

and 5-HT<sup>3</sup>

linergic agonist pilocarpine (2 mg/kg, i.p.), the M<sup>1</sup>

the non-selective dopamine D<sup>2</sup>

R ago-

119

R agonist

Role of Calcium in Vomiting

R-preferring agonist quinpirole (2 mg/kg, i.p.),

R agonist GR73632 (5 mg/kg, i.p.). The vomiting

**R antagonists when combined with** 

R binding site itself (i.e., the orthosteric site) but

receptor channel complex. Furthermore, 5-HT release

receptor-selective agonist

Rs and LTCCs


http://dx.doi.org/10.5772/intechopen.78370

R agonist apomorphine (2 mg/kg, i.p.), the nonselective cho-
