INVOLVEMENT OF NEUROKININS IN THE NONCHOLINERGIC RESPONSE TO ACTIVATION OF 5-HT3 AND 5-HT4 RECEPTORS IN GUINEA-PIG ILEUM

1 The involvement of neurokinins in the non-cholinergically-mediated contractile response induced by stimulation of 5-HT3 and 5-HT4 receptors has been examined in the longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum. 2 The 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT), showed a lower potency in this preparation than the more selective 5-HT4 receptor agonist 5-methoxytryptamine. The effect of bath drugs was markedly reduced by atropine. 3 Substance P (SP) and neurokinin B (NKB) produced biphasic concentration-response curves in the preparation. Neurokinin A (NKA), the NK1 receptor agonist, [Sar(9),Met(O-2)11]SP and the NK3 receptor agonist, senktide yielded monophasic concentration-response curves. 4 After desensitization of the NK1 receptor with SP or [Sar(9),met(O-2)11]SP, in the presence of atropine, the contractile response to 2-methyl-5-HT was entirely blocked, Desensitization of NK3 receptors with NKB, also in the presence of atropine, fully suppressed the 5-HT4 receptor-mediated contraction evoked by 5-methoxytryptamine. 5 In preparations prelabelled with [H-3]-choline, SP produced a concentration-dependent increase in tritium overflow, an index of [H-3]-acetylcholine release, while an inverse relationship was found with NKB. At low neurokinin concentrations, the releasing effect of NKB was much more marked. 6 It is suggested that in the response to 5-HT3 receptor stimulation, there is a role for SP and acetylcholine. NKB appears to be preferentially involved in the release of acetylcholine elicited by stimulation of 5-HT4 receptors.