Andoh Tsugunobu, Kuraishi Yasushi
Department of Applied Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Br J Pharmacol. 2003 Jan;138(1):202-8. doi: 10.1038/sj.bjp.0705004.
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.
1 P物质（SP）分别在人和小鼠中引发瘙痒及与瘙痒相关的反应。在小鼠中，NK(1)速激肽受体参与SP诱导的与瘙痒相关的反应、抓挠，而肥大细胞不起关键作用。本研究旨在阐明一氧化氮（NO）在小鼠SP诱导抓挠中的作用。2 皮内注射SP（100 nmol/部位(-1)）可引起小鼠抓挠，静脉注射一氧化氮合酶（NOS）抑制剂N(G)-硝基-L-精氨酸甲酯（L-NAME）可抑制该反应，但其无活性对映体D-NAME则无此作用。皮内注射L-NAME（100 nmol/部位(-1)）、另一种NOS抑制剂7-硝基吲唑（10 nmol/部位(-1)）和NO清除剂血红蛋白（0.01 - 10 nmol/部位(-1)）也可抑制SP诱导的抓挠。3 L-NAME（100 nmol/部位(-1)）不影响皮内注射5-羟色胺（100 nmol/部位(-1)）诱导的抓挠。4 皮内注射L-精氨酸（300 nmol/部位(-1)）和NO供体(+/-)-(E)-4-乙基-2-[(E)-羟基亚氨基]-5-硝基-3-己烯酰胺（NOR3；100 nmol/部位(-1)）可增强SP诱导的抓挠。单独皮内注射L-精氨酸（1 - 1000 nmol/部位(-1)）或NOR3（1 - 100 nmol/部位(-1)）对抓挠无影响。5 皮内注射SP（10 - 100 nmol/部位(-1)）可使小鼠皮内NO浓度呈剂量依赖性增加。SP诱导的NO水平升高受到L-NAME和NK(1)速激肽受体拮抗剂L-668,169的抑制，但不受NK(2)速激肽受体拮抗剂L-659,877的抑制。6 SP（1 - 10 μM）可诱导培养的人角质形成细胞产生NO，且SP诱导的NO产生受到L-NAME和L-668,169的抑制。7 我们得出结论，皮内注射SP可增加皮肤中的NO，可能是通过作用于表皮角质形成细胞上的NK(1)速激肽受体，且NO可增强SP诱导的与瘙痒相关的反应。
