Presynaptic inhibition produced by histamine at nicotinic synapses in enteric ganglia

Abstract

Intracellular methods were used to record last excitatory postsynaplic potentials in myenteric neurons of the guinea-pig small intestine in vitro. The excitatory postsynaptic potentials were suppressed by hexamethonium. mimicked by acetylcholine and assumed to be mediated by nicotinie eholinergie receptors. Application of histamine either by addition to the superfusion solution or by focal application from One-tipped pipettes reversibly reduced the amplitude or abolished the excitatory postsynaptie potentials. Postsynaptie responses to focal application of acetylcholine by pressure ejection from micropipettes were either unaffected or were potentiated by histamine Failure of histamine to affect antidromic action potentials excluded a local anesthetic action on the presynaptic libers. Neither 2-methylhistamine nor dimaprit, which are selective H2 and H2 agonists respectively, suppressed the excitatory postsynaptic potentials when applied in concentrations nearly one hundred times greater than theed50 for histamine. The selective H1 and H2 antagonists, pyrilamine and cimetidine did not suppress the inhibitory action of histamine when applied separately or in combination. Based on these results, the presynaptic receptors involved in this inhibitory mechanism appeared to be of a pharmacologically atypical histamine receptor subtype. The putative histamine agonist. N,α-methylhistamine, which has been reported to have high stereoselectivity and activity for a receptor subtype classified as H3, potently reduced or abolished the excitatory postsynaptic potentials. Theed50 for N,α-methylhistamine was 8.8 nM compared to aned50 of 220 nM for histamine. Burimamide. a histamine antagonist with higher activity at putative H3 receptors than H2 receptors, effectively reversed the inhibitory action of histamine on the excitatory postsynaptic potentials.Our results suggest that histamine acts at presynaptic terminals of nicotinie eholinergic synapses to suppress the release of acetylcholine.