An antinociceptive effect of capsaicin in the adult mouse mediated by the NH₂-terminus of substance P

Capsaicin in the adult animal is believed to evoke a massive release of substance P (SP) and a subsequent loss of primary afferent C-fiber activity. Given the antinociceptive effect of SP N-terminal metabolites, the present experiments were designed to compare behavioral and nociceptive responses after treatments with capsaicin or the SP NH₂-terminal fragment, SP(1-7), and to determine whether they share a common mechanism of action. When adult mice were tested using the hot-plate assay, 24 hr after intrathecal injections of either capsaicin (0.3-2.6 nmol) or SP(1-7) (22.5 pmol-10 nmol), a dose-related antinociception was observed. The caudally directed biting and scratching behaviors induced by 1 nmol of capsaicin injected intrathecally were also greatly reduced 24 hr after either 2.6 nmol of capsaicin or 10 nmol of SP(1-7). Pretreatment with an antagonist of the NH₂-terminus of SP, [D- Pro²,D-Phe⁷]-SP(1-7), prevented the long-term effects of capsaicin and of SP(1-7) on capsaicin-induced behaviors in our paradigm at doses that the COOH-terminal antagonist of neurokinin activity, [D-Pro²,D-Trp^7,9]-SP, did not. The antinociceptive effect of capsaicin in the adult animal is, therefore, mimicked by SP(1-7) and attenuated by [D-Pro², D-Phe⁷]-SP(1-7), suggesting that the NH₂-terminus of SP and its NH₂-terminal metabolites, released in response to capsaicin, may contribute to the mediation of capsaicin's antinociceptive effect.