Although the cholinergic neurotransmitter system per se is not directly involved in chemotherapy-induced vomiting (see section 2.1), dopaminergic and serotonergic mechanisms do appear to be important downstream in cannabinoids' antiemetic actions. Indeed, in the feline, nabilone dose-dependently prevents emesis produced by the dopamine D2 receptor agonist apomorphine (London et al., 1979). In a similar manner, A9-THC prevents vomiting produced by dopamine D2/D3 receptor agonists such as apomorphine, quinpirole, quinelorane and 7-OH DPAT in the least shrew (Darmani, unpublished observations). In this context, the least shrew seems to be an excellent dopamine animal model of emesis since the cited selective and nonselective dopamine D2 receptor agonists can potently induce emesis in this species, whereas D2 antagonists prevent the induced behavior (Darmani et al., 1999). As discussed earlier, clinical findings further underscore the role of blockade of the dopaminergic system in the antiemetic properties of cannabinoids since a combination of a cannabinoid with a D2 antagonist appears to be a superior antiemetic regimen than when each drug is given alone to patients receiving chemotherapy (Garb et al., 1980; Lane et al., 1990). Other lines of evidence also indicate interactions between these two neurotransmitter systems. For example, the aminoalkylindole cannabinoid WIN 55, 212-2, can reverse the dopamine D2 receptor-mediated alleviation of akinesia in the reserpine-treated model of Parkinson's disease (Maneuf et al., 1997). Secondly, the nonclassical cannabinoid CP 55, 940, at doses which do not produce catalepsy, can potentiate the cataleptic effect of the D2 antagonist raclo-pride (Anderson et al., 1996).
Involvement of serotonergic mechanisms in the antiemetic properties of can-nabinoids is highlighted by several studies. For example, nanomoler concentrations of several classes of cannabinoids (CP55,940; CP56,667; anandamide and WIN 55, 212-2), block the 5-HT3 receptor-mediated inward currents induced by 5-HT3 receptor agonists in a dose-dependent but noncompetitive manner in rat nodose ganglion neurons (Fan, 1995). Secondly, cannabinoids reduce 5-HT synthesis, levels and turnover in several regions of rodent brain (Bannergee et al., 1975; Ho et al., 1971; Johnson et al., 1976; Molina-Holgado et al., 1993; Taylor and Fennessy, 1982). Moreover, the CBX antagonist SR 141716A, precipitates withdrawal-like behaviors both in cannabinoid tolerant rats (Aceto et al., 1995; Tsou et al., 1998) and drug naive rodents (Cook et al., 1998; Darmani and Pandya, 2000). Many of the induced behaviors have serotonergic origin. Not only the selective serotonin 5-HT2A antagonist SR 46349B, but also A9-THC, prevented some of these SR 141716A-induced behaviors in mice (Darmani and Pandya, 2000). Furthermore, several cannabinoids (CP 55, 940; HU 210; WIN 55, 212-2; A9-THC and A8-THC) potently block the head-twitch and ear-scratch behaviors produced by the 5-HT2A agonist DOI, in mice (Darmani, 2000b). Thus, it seems that cannabinoids generally reduce serotonin function via CBX receptors. SR 141716A not only induces vomiting (Darmani, 2001a), but also produces some of these behaviors in the lesser shrew (Darmani, unpublished findings). As in the case of SR 141716A-induced serotonergic behaviors, structurally diverse cannabinoids also block SR 141716A-induced emesis (Darmani, 2001a). Despite the discussed serotonergic findings, as yet there is no basic or clinical study to either compare the antiemetic efficacy of selective 5-HT3
receptor antagonists against cannabinoids in chemotherapy-induced vomiting, or to determine whether a combination of these antiemetics may have synergistic action. In this context, the least shrew has already been evaluated as an excellent animal model for the induction emesis for 5-HT3 receptor agonists (Darmani, 1998). Furthermore, the latter study shows that 5-HT3 receptor antagonists can prevent emesis produced by the chemotherapeutic agent cisplatin.
Cannabinoid agonists such as WIN 55, 212-2 and methanandamide are also effective antiemetics in preventing morphine-induced emesis in the ferret (Simoneau et al., 2001; Van Sickle 2001). In addition, the antiemetic effects of these cannabinoids were reversed by the CBr(AM 251) but not by the CB2-(AM 630) receptor antagonist. Although the effect of high doses of AM 251 was not investigated, a 5 mg/kg dose of this CBX antagonist failed to evoke emesis, but was shown to potentiate the frequency of morphine-induced emesis in the ferret (Van Sickle, 2001). As discussed earlier, the well investigated CBX receptor antagonist SR 141716A but not the CB2 receptor antagonist SR 144528 produces significant emesis by itself at doses greater than 10 mg/kg (Darmani 2001a). Both AM 251 and SR 141716A also act as inverse agonists and their emetic effects could be caused by inhibition of the binding of an antiemetic endocannabinoid or via a reduction in the activity of a constitutively active cannabinoid CBX receptor.
Finally, tachykinin NKX receptors may also play a role in the antiemetic action of cannabinoids. Recent results from this laboratory show that the NKj antagonist CP 94, 994 attenuated the ability of the CBX antagonist, SR 141716A, to produce scratching and head-twitching behaviors in mice (Darmani and Pandya, 2000). As already discussed, such antagonists possess broad spectrum antiemetic action and are potent blockers of chemotherapy-induced vomiting both in animals and man (Bountra et al., 1996; Navari et al., 1999). In addition, chronic administration of A9-THC increases mRNA levels of the preferential tachykinin NKX agonist, substance P (Mailleux and Vanderhaegen, 1994).
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