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.02 mg/kg, iv) and nabilone (0.025 0.1 mg/kg,iv) protected cats against cisplatin-induced vomiting and reduced the numberof vomiting episodes among cats not protected in a dose-dependent manner.PigeonsAn early study [65] with pigeons demonstrated that the non-psychotropic syn-thetic cannabinoid, HU-211, was more effective than "9 -THC in suppressingcisplatin-induced vomiting.The anti-emetic effect of HU-211 was U-shapedover a narrow dose range, with maximal efficacy at 2.5 and 3 mg/kg, adminis-tered subcutaneously (sc).More recently, the potent psychoactive cannabinoid,HU-210 (0.0125 0.05 mg/kg, sc) has also been reported to suppress cis-platin-induced vomiting in the pigeon [66].FerretsOne of the most widely used animal models of emesis is the ferret.In thismodel, morphine-induced emesis [33] was suppressed by the syntheticcannabinoid agonist WIN-55,212-2 (0.03 0.13 mg/kg, sc) and this effect wasreversed by the selective CB1 receptor antagonist, AM-251.Van Sickle et al.[34] report that the emesis produced by morphine-6-glucuronide (M6G; sc) inferrets was also inhibited by "9-THC [1 mg/kg, administered intraperitoneally(ip)], WIN-55,212-2 (1 mg/kg, ip) and methanandamide (3 mg/kg, ip), and thatthis anti-emetic effect was also reversed by AM-251 (5 mg/kg, ip).AlthoughAM-251 did not produce emetic episodes on its own, it did potentiate the eme-togenic effects of M6G [34].More recently, "9-THC (0.05 1 mg/kg, ip)dose-dependently inhibited the emetic actions of cisplatin [35].Furthermore,"9-THC applied to the surface of the brain stem also inhibited emesis inducedby intragastric hypertonic saline [35].ShrewsInsectivores, such as the shrew, are the closest extant relatives to primates aswell as the oldest group of eutherians.Insectivores have sensitive emeticreflexes.Shrews are smaller than carnivores (such as cats, dogs and ferrets)Cannabinoids: effects on vomiting and nausea in animal models 189that have typically been used to evaluate the anti-emetic properties of drugsand, therefore, are easier to maintain in a laboratory.Considerable recent work by Darmani and colleagues [24 29] has evaluatedthe potential of different groups of cannabinoids to inhibit emesis induced bytoxins in C.parva (the least shrew), which weighs 4 6 g.Cisplatin-inducedemesis was inhibited by WIN-55,212-2 (1 5 mg/kg, ip) and "9-THC(1 10 mg/kg, ip) in a dose-dependent manner with similar potency [25, 26].However, the synthetic cannabinoid CP-55,940 (0.025 0.3 mg/kg, ip) morepotently antagonized cisplatin-induced vomiting than WIN-55,212-2 or"9-THC and also had a higher affinity for the CB1 receptor [29].The syntheticHU-210 has a higher affinity for the CB1 receptor than CP-55,940, but has notbeen systematically evaluated for its anti-emetic capacity in the shrew model.Emesis induced by the precursor to serotonin, 5-hydroxytryptophan (5-HTP)(100 mg/kg, ip) was suppressed by "9-THC [28] at doses of 5 20 mg/kg, ip;however, a dose of 20 mg/kg, ip, of "9-THC was required to suppress the eme-sis produced by 5-HT (5 mg/kg, ip) and the selective 5-HT3 agonist2-methylserotonin (5 mg/kg, ip).Therefore, cannabinoids appear to suppressthe emetic reaction to drugs that activate the serotonin system in the least shrew.Since cannabinoid agonists prevent emesis, Darmani [24] predicted thatblockade of the CB1 receptor would induce vomiting.Indeed, at a dose of10 mg/kg, ip, or 40 mg/kg, sc, SR-141716 induced vomiting in the least shrew;on the other hand, the CB2 receptor antagonist, SR-144528, did not producevomiting at any dose tested.WIN55,212-2 (minimal dose 10 mg/kg, ip) wasmore effective than "9-THC (minimum dose 20 mg/kg, ip) in preventingSR-141716-induced vomiting [24, 29], which was also prevented byCP-55,940 (1 mg/kg, ip).The selective CB1 receptor antagonist SR-141716blocked the anti-emetic activity of cannabinoids at low doses [24 29] and pro-duced vomiting on its own at higher doses in least shrews [24], suggesting thatthe endogenous cannabinoid system plays a role in the regulation of emesis.Darmani [27] has also shown that the endocannabinoid 2-AG is a potentemetogenic agent, whereas anandamide may cause weak anti-emetic effects[27, 35].The emetic effects of 2-AG were inhibited by CP-55,940(0.05 0.1 mg/kg, ip), WIN-55,212-2 (1 5 mg/kg, ip), "9-THC (2.5 5 mg/kg,ip), anandamide (5 mg/kg, ip), methanandamide (10 mg/kg, ip) and SR-141716(2.5 5 mg/kg, ip), but not by CBD (10 20 mg/kg, ip).These results suggestthat endogenous cannabinoids may also play a role in promoting emesis.Over the past number of years, the S.murinus (house musk shrew) has beenused as a model for emesis research [4, 6, 7].These shrews weigh 30 60 g incontrast to the 4 6 g of the least shrew.Like rats, Suncus will avoid a flavorpaired with lithium chloride [69]; however, unlike rats, these animals vomit inresponse to toxins, even though they possess similar neural circuitry in theemetic regions of the brain as rats [70].In a series of experiments, Parker et al.[31] evaluated the emetogenic potential of lithium in Suncus and the ability oftwo principal cannabinoids found in marijuana, the psychoactive "9-THC andthe nonpsychoactive CBD, to reverse lithium-induced emesis.A prior study190 L.A.Parker et al.[27] indicated that, unlike other cannabinoids tested including "9-THC, CBD(10 and 20 mg/kg, ip) did not reverse retching and vomiting induced by theendogenous cannabinoid, 2-AG, in the much smaller least shrew.It has alsobeen reported to be ineffective at inhibiting gastric motility in mice [71].However, we had previously shown that CBD did prevent the establishment oflithium-induced conditioned gaping in rats [38], a putative rat model of nausea(reviewed below).We [31] found that "9-THC produced a dose-dependentsuppression of lithium-induced vomiting with higher doses producing greatersuppression than lower doses.CBD, however, produced a biphasic effect withlower doses (5 and 10 mg/kg, ip), producing suppression and higher doses (20and 40 mg/kg) producing enhancement of lithium-induced vomiting [ Pobierz całość w formacie PDF ]