Tltc number of emetic episodes reported in table I for 5110 pg kg of rhc latter drug was significantly higher than that observed in the time course experiments . This discrepancy may be due at least in part to a lower pcrccntage of vomiting birds in the latter experiment . In the prcscnt study. the pigeon proved to be a reproducible model as far as the emetic response to cisplatin is concerned: dose dependent cmesis was observed in the dose range previously found to be effective in the pigeon by Feigenbaum et al although these authors found that cisplatin did not in ice rmcsis at the dose of 5 mg kg. This discrepancy may be explained on the basis of differences in the methods used to assess emesis: Feigenbaum et al. did not consider retching as a part of the emesis complex. This might have led to an underestimation of the total number of responses per bird, compared to our approach. Cisplatin displayed the same efficacy in pigeons and in ferrets. with IO mg kg i.v. being effective in producing profuse emesis in both species . As in ferrets, a serotonergic mechanism also seems to be involved in pigeons, since in the present study pretreatment with pCPA prevented cisplatin emesis, thus indicating that the presence of 5 HT is necessary for vomiting to occur.
A serotonergic mechanism for cisplatin induced emesis has, indeed. been well documented in other species. Cisplatin has been shown to release 5 HT from the small intestine in ferrets . Similar findings Romidepsin distributor have been obtained with isolated segments of guinea pig small intestine . The local release of 5 HT in the upper GI tract can, through peripheral 5 HT, receptors, stimulate vagal nerve fibres. These fibres form the afferent arm of the vomiting reflex, since vagotomy abolishes cisplatin induced vomiting in ferrets . A central site of action of cisplatin in inducing emesis has also been proposed, as the injection of 5 HT, receptor antagonists in the area postrema of the ferret can inhibit cisplatin induced emesis . However, it must be pointed out that any attempt to localize a central or peripheral site of action of cisplatin may be misleading, since autoradiographic studies show that, at least in the rat, 5 HT, receptors are present along the vagus nerve .
PD0332991 selleck Data from humans, based on systemic 5 HT turnover assessment, confirm the role of 5 HT in cisplatin emesis . As far as the protective effects of 5 HT, receptor antagonists on emcsis are concerned, the results of the present study indicate the existence of marked discrepancies between the pigeon and other species. In fact, while in ferrets and humans 5 HT, receptor antagonists display strong anti cmctic activity . These discrepancies are clearly difficult to explain on the basis of present knowledge.