Identification of a novel receptor mediating substance P-induced behavior in the mouse

To determine whether opioid receptors or the more recently characterized naloxone-sensitive substance P (SP) N-terminal binding sites play a role in desensitization to the behavioral effects of SP, we assessed the effects of selective antagonists at mu-(naloxonazine and beta-funaltrexamine), delta- (naltrindole) and kappa- (nor-binaltorphimine) opioid receptors, as well as the effect of [D-Pro2,D-Leu7]SP-(1-7) D-SP-(1-7) (D-SP (1-7)), an inhibitor of [3H]SP-(1-7) binding, on behaviors induced by intrathecally administered SP in mice. Whereas naloxone, a non-selective opioid antagonist, inhibited the development of behavioral desensitization to SP, the response to repeated SP administration remained unaffected by pretreatment with selective opioid antagonists. Like naloxone, however, the SP-(1-7) antagonist inhibited SP-induced desensitization. The protection against desensitization to SP by D-SP-(1-7), but not by selective antagonists of mu, delta or kappa receptors, suggests that desensitization to the behavioral effects of SP does not appear to be mediated by an action at an opioid receptor but by an action at the SP-(1-7) binding site.