Antiemetic Effects of Serotonergic 5-HT1A-Receptor Agonists in Suncus Murinus

Abstract

ABSTRACT-The antiemetic effects of six serotonergic 5-HTIA-receptor agonists, 8-hydroxy-2-(di-n-pro pylamino)tetrarin (8-OH-DPAT), 4-{4-[4-(2-pyrimidinyl)piperazin-l-yl]butyl}-2,3,4,5-tetrahydro-l,4-benzo xazepine-3,5-dione (SUN8399), buspirone, gepirone, ipsapirone and tandospirone, against motion sickness were investigated in Suncus murinus. Subcutaneous injection of all six agonists completely and dose-dependently suppressed motion-induced emesis. Pretreatment with 8-OH-DPAT or SUN8399 dose dependently inhibited emesis elicited by nicotine (4.0 mg/kg, s.c.), veratrine (0.7 mg/kg, s.c.), cisplatin (20 mg/kg, i.p.) and copper sulfate (40 mg/kg, p.o.). These results suggest that serotonergic 5-HTIA-receptor agonists are effective as anti-motion sickness drugs, and these drugs may block a common mechanism(s) for the emetic reflex of the suncus because the antiemetic effects of the 5-HT1A-receptor agonists were exerted irrespective of the stimulus.

Migraine and motion sickness: What is the link?

“…Triptans may evoke analgesic anti-migraine activity in the trigeminal nucleus caudalis, and anti-emetic effects in the NTS, by acting on the numerous 5-HT 1 receptor sites in these locations (Pascual, del Arco, Romon, del Omo, Castro and Pazos, 1996;Hoskin et al, 2004). Serotonin prevents motioninduced emesis in animals (Javid and Naylor, 2006;Okada, Saito and Matsuki, 1996), and 5-HT 1A agonists inhibit vomiting during motion sickness in cats (Lucot, 1989;Yates, Miller and Lucot, 1998) and the Asian musk shrew (Okada, Torii, Saito and Matsuki, 1994). However, findings in animal research do not necessarily extrapolate to clinical efficacy in humans (Reid, Sciberras, Gertz, Reinhardt, Lui, Golding and Stott, 1998;Hasler, 1999;Peroutka, 2005).…”

Blockade of motion‐ and cisplatin‐induced emesis by a 5‐HT2 receptor agonist in Suncus murinus

“…Selective antagonists for the 5-HT3 receptor inhibit emesis induced by cancer chemotherapeutic agents, such as cisplatin, in ferrets (Costall et al, 1986), dogs (Smith et al, 1986), cats (Lucot, 1989) and Suncus (Torii et al, 1991a) and these antagonists have been used clinically. It has also been reported that 5-HT,A receptor agonists can block emesis induced by motion and several emetic drugs in cats (Lucot & Crampton, 1989) and Suncus (Okada et al, 1994).…”

“…In cats, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone suppress vomiting elicited by motion, cisplatin and xylazine (Lucot & Crampton, 1989). In Suncus, several 5-HTA receptor agonists inhibited emesis not only elicited by cisplatin but also by other stimuli (Okada et al, 1994). However, it is not likely that the antiemetic effect of DOI is mediated via 5-HTA receptors, since this compound has very little affinity for 5-HTIA receptors (Hoyer, 1988a).…”

Comparative efficacy of a single oral dose of ondansetron and of buspirone against cisplatin-induced emesis in cancer patients

“…Recent studies in laboratory animals indicate that 5-HTlA receptor agonists (buspirone, 8-OH-DPAT, flesinoxan, genpirone) have antiemetic activity against emetic stimuli acting via different pathways (Lucot andCrampton, 1987, 1989;Milano and Gregot, 1992;Okada et al, 1994). High concentrations of 5-HTlA binding sites and of receptor mRNA have been found in the nucleus tractus solitarius, an important brain area in the control of emesis (Lucot, 1992).…”

“…Recent studies indicate that, in addition to 5-HT3 receptors, other serotonin receptor subtypes may play a role in emesis. In laboratory animals, activation of 5-HTlA receptors by a single dose of 8-hydroxy-2-(di-n-propyl amino)tetralin(8-OH-DPAT), buspirone or other 5-HTIA agonists suppresses emesis induced by motion sickness, cisplatin, ac2-adrenergic receptor agonists, nicotine, veratrine, copper sulphate or stimulation of vagal afferents (Lucot andCrampton, 1987, 1989;Milano and Gregot, 1992;Okada et al, 1994). The antiemetic effects of 5-HTlA receptor agonists have not been explored in humans.…”