Nitric oxide enhances substance P-induced itch-associated responses in mice.
1 Substance P (SP) elicits itch and itch-associated responses in humans and mice, respectively. In mice, NK(1) 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. 2 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 N(G)-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. 3 L-NAME (100 nmol site(-1)) did not affect scratching induced by an intradermal injection of 5-hydroxytryptamine (100 nmol site(-1)). 4 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. 5 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 NK(1) tachykinin receptor antagonist L-668,169, but not by the NK(2) tachykinin receptor antagonist L-659,877. 6 SP (1-10 micro M) elicited NO production in cultured human keratinocytes and the SP-induced NO production was inhibited by L-NAME and L-668,169. 7 We conclude that intradermal SP increases NO in the skin, possibly through the action on NK(1) tachykinin receptors on the epidermal keratinocytes and that NO enhances SP-induced itch-associated responses.
Andoh
Tsugunobu
T
Department of Applied Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Kuraishi
Yasushi
Y
D000328:Adult; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D064729:Neurokinin-1 Receptor Antagonists; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011537:Pruritus / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000633:toxicity*
D004791:Enzyme Inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D009569:Nitric Oxide; D013373:Substance P; D019001:Nitric Oxide Synthase