Nitric oxide enhances substance P‐induced itch‐associated responses in mice

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Abstract
Substance P (SP) elicits itch and itch-associated responses in humans and mice, respectively. In mice, NK1 tachykinin receptors are involved in SP-induced itch-associated responses, scratching, and mast cells do not play a critical role. The present study was conducted to elucidate the role of nitric oxide (NO) on SP-induced scratching in mice. An intradermal injection of SP (100 nmol site−1) elicited scratching in mice, and it was suppressed by an intravenous injection of the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME), but not by its inactive enantiomer D-NAME. Intradermal injections of L-NAME (100 nmol site−1), another NOS inhibitor 7-nitroindazole (10 nmol site−1) and the NO scavenger haemoglobin (0.01–10 nmol site−1) also inhibited SP-induced scratching. L-NAME (100 nmol site−1) did not affect scratching induced by an intradermal injection of 5-hydroxytryptamine (100 nmol site−1). Intradermal injections of L-arginine (300 nmol site−1) and the NO donor (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3; 100 nmol site−1) increased scratching induced by SP. Intradermal injections of L-arginine (1–1000 nmol site−1) or NOR3 (1–100 nmol site−1) alone were without effects on scratching. Intradermal injections of SP (10–100 nmol site−1) increased the intradermal concentration of NO in a dose-dependent manner in mice. An increase in NO levels induced by SP was inhibited by L-NAME and the NK1 tachykinin receptor antagonist L-668,169, but not by the NK2 tachykinin receptor antagonist L-659,877. SP (1–10 μM) elicited NO production in cultured human keratinocytes and the SP-induced NO production was inhibited by L-NAME and L-668,169. We conclude that intradermal SP increases NO in the skin, possibly through the action on NK1 tachykinin receptors on the epidermal keratinocytes and that NO enhances SP-induced itch-associated responses. British Journal of Pharmacology (2003) 138, 202–208. doi:10.1038/sj.bjp.0705004