Regulation of substance P release mediated via prejunctional histamine H 3 receptors

Abstract

The involvement of the histamine H 3 receptor in the regulation of substance P release in neurogenic inflammation was studied by using rat hindpaw skin. R-(−)-α-Methylhistamine, a specific histamine H 3 receptor agonist, significantly inhibited the increased vascular permeability induced by antidromic electrical stimulation of the sciatic nerve in a dose-dependent manner at doses of 0.5–3 mg/kg (i.v.), and thioperamide (2 mg/kg i.p.), a specific histamine H 3 receptor antagonist, prevented the inhibitory effect of R-(−)-α-methylhistamine. The antidromic stimulation also caused a significant increase in immunoreactive substance P release in the subcutaneous (s.c.) perfusate in the rat hindpaw. R-(−)-α-Methylhistamine (0.25–2 mg/kg) dose dependently inhibited the increase in release of immunoreactive substance P, and thioperamide (2 mg/mg i.p.) antagonized it. Perfusion of histamine (10 −3 M) elicited a significant increase of immunoreactive substance P release in the perfusate, which was reduced by R-(−)-α-methylhistamine and the antagonism of thioperamide was also observed. Histamine (in the presence of histamine H 1 and H 2 receptor antagonists) had an inhibitory effect on the electrically evoked release of immunoreactive substance P. These results strongly support the hypothesis that histamine regulates substance P release via prejunctional histamine H 3 receptors that are located on peripheral endings of sensory nerves.