Intrathecal histamine induces spinally mediated behavioral responses through tachykinin NK₁ receptors

Intrathecal injection of histamine elicited a behavioral response consisting of scratching, biting and licking in conscious mice. Here, we have examined the involvement of substance P (SP) by using intrathecal injection of tachykinin neurokinin (NK)₁ receptor antagonists and SP antiserum. Histamine-induced behavioral response was evoked significantly 5-10 min after intrathecal injection and reached a maximum at 10-15 min. Dose-dependency of the induced response showed a bell-shaped pattern from 200 to 3200 pmol, and maximum effect was observed at 800-1000 pmol. The H₁ receptor antagonist, d-chlorpheniramine and pyrilamine but not the H₂ receptor antagonists, ranitidine and zolantidine, inhibited histamine-induced behavioral response. The NK₁ receptor antagonists, CP-99,994, RP-67580 and sendide, inhibited histamine-induced behavioral response in a dose-dependent manner. A significant antagonistic effect of [D-Phe⁷, D-His⁹]SP (6-11), a selective antagonist for SP receptors, was observed against histamine-induced response. The NK₂ receptor antagonist, MEN-10376, had no effect on the response elicited by histamine. Pretreatment with SP antiserum resulted in a significant reduction of the response to histamine. No significant reduction of histamine-induced response was detected in mice pretreated with NK A antiserum. The present results suggest that elicitation of scratching, biting and licking behavior induced by intrathecal injection of histamine may be largely mediated by NK₁ receptors via H₁ receptors in the spinal cord.