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 μ- (naloxonazine and ß-funaltrexamine), δ- (naltrindole) and κ- (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 μ, δ or κ 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.