Vagal afferent-mediated inhibition of a nociceptive reflex by i.v. serotonin in the rat. II. Role of 5-HT receptor subtypes.

Abstract In the rat, intravenous (i.v.) serotonin (5-HT) is a noxious stimulus which produces distinct vagal afferent-mediated pseudoaffective responses, a passive avoidance behavior, a vagal afferent-mediated inhibition of the nociceptive tail-flick (TF) reflex and a complex triad of cardiovascular responses. In the present study, we have used a variety of 5-HT receptor antagonists to characterize the receptor subtype(s) in the rat that mediate (1) inhibition of the TF reflex and (2) the cardiovascular responses produced by i.v. 5-HT. 5-HT produced a dose-dependent (3–72 μg/kg, i.v.) inhibition of the TF reflex (ED50 = 15.3 ± 0.7 μg/kg). Following administration of the 5-HT2 receptor-selective antagonists ketanserin (50–250 μg/kg, i.v.) or xylamidine (10–100 μg/kg, i.v.), or the 5-HT3 receptor-selective antagonists ICS 205–930 (50–250 μg/kg, i.v.) or MDL 72222 (25–250 μg/kg, i.v.), there appeared to be a parallel shift of the 5-HT dose-response curve to the right. Following co-administration of xylamidine (50 μg/kg, i.v.) with ICS 205–930 (100 μg/kg, i.v.), the 5-HT-induced inhibition of the TF reflex was completely abolished at all doses of 5-HT tested (3–288 μg/kg, i.v.). In contrast, administration of the centrally acting 5-HT2 receptor-selective antagonist LY 53857 (10–100 μg/kg, i.v.) or the non-specific receptor antagonist methysergide (25–500 μg/kg, i.v.) resulted in a dose-dependent, but not parallel shift of the 5-HT dose-response curve to the right. The maximal doses of LY 53857 and methysergide tested (250 μg/kg and 500 μg/kg, respectively) completel abolished the effects of 5-HT (3–288 μg/kg, i.v.). Administration of the α1-adrenoceptor antagonist prazosin (25–100 μg/kg, i.v.) failed to alter the 5-HT dose-response curve, indicating that the effects of ketanserin were due to blockage of 5-HT2 receptors rather than α1 receptors. Administration of each of the antagonists also produced marked, but selective effects on components of the complex cardiovascular response to i.v. 5-HT. Each of the 5-HT3 receptor selective antagonists (ICS 205–930 or MDL 72222) produced a dose-dependent attenuation of the Bezold-Jarisch reflex-mediated hypotension and bradycardia, and each of the 5-HT2 receptor selective antagonists (xylamidine, ketanserin or LY 53857) produced a dose-dependent attenuation of the pressor response. The non-specific 5-HT receptor antagonist methysergide produced a dose-dependent attenuation of the 5-HT-induced pressor response. Prazosin resulted in a significant increase in the magnitude of the 5-HT-induced Bezold-Jarisch reflex bradycardia. Saline did not alter the cardiovascular response to i.v. 5-HT. Prazosin (100 μg/kg, i.v.) and ketanserin (250 μg/kg, i.v.) significantly lowered resting mean arterial blood pressure while ICS 205–930 (250 μg/kg, i.v.) significantly raised resting mean arterial blood pressure. The results of this study clearly show that i.v. 5-HT-induced inhibition of the TF reflex requires activation of peripheral 5-HT2 and 5-HT3 receptors. In addition, these studies raise the possibility that central 5-HT2 receptors may also be involved in the 5-HT-induced vagally mediated inhibition of the TF reflex.