Neuronal 5-HT receptors in the periphery.

5-Hydroxytryptamine (5-HT) induces responses in neurones from all branches of the mammalian peripheral nervous system. Responses may be excitatory or inhibitory and are mediated through at least four distinct receptor sites. One receptor mediates excitation in motoneurones and preganglionic sympathetic neurones and can be designated a D (or possibly 5-HT2) receptor since "classical" antagonists such as methysergide, metergoline or cinanserin are potent and selective antagonists at this site. A second receptor mediating neuronal excitation can be positively identified on the basis of susceptibility to blockade by small concentrations of 1 alpha H,3 alpha,5 alpha H-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222) and the weak or negligible affinity, relative to 5-HT, of certain agonists such as 5-methoxytryptamine. Such sites mediate depolarization of sympathetic and parasympathetic neurones and excitation of both the cell bodies and terminals of primary afferent fibres. A third receptor, mediating neuronal excitation, is the classical M-receptor of Gaddum and Picarelli, at this stage clearly identified only on postganglionic parasympathetic neurones of the guinea-pig myenteric plexus. These sites can be differentiated from other excitatory 5-HT receptors since MDL 72222 is neither potent nor selective as an antagonist and 5-methoxytryptamine approaches the potency of 5-HT as an agonist. (3 alpha-Homotropanyl)-1-methyl-5-fluoro-indole-3-carboxylic acid is a potent, surmountable antagonist of 5-HT at the M-receptor of the ileum, but is non-selective. Neuronal inhibitory responses have been observed using electrophysiological techniques or by monitoring the decrease in depolarization-evoked release of transmitter in enteric, parasympathetic and sympathetic neurones. Largely negative results, using selective agonists and antagonists, allow the receptor(s) mediating inhibition to be clearly differentiated from the three neuronal excitatory receptors for 5-HT. Comparison of relative potencies of agonists suggests similarities with the 5-HT1 recognition site of the central nervous system; no selective antagonist has yet emerged to permit their positive identification.