Use of NK(1) knockout mice to analyze substance P-induced edema formation.
The mechanisms involved in tachykinin-induced neurokinin-1 (NK(1)) receptor-mediated edema formation have been studied in anesthetized wild-type and NK(1) knockout mice. Intradermally injected substance P (30-300 pmol), NK(1) agonists septide (3-30 pmol) and GR-73632 (3-30 pmol), and the mast cell-degranulating agent, compound 48/80 induced dose-dependent edema in wild-type skin, measured by the accumulation of intravenously injected (125)I-labeled albumin. Septide was 3-10x more potent than substance P. The tachykinins were inactive in knockout mice, but compound 48/80 induced a significantly greater edema (P < 0.05) than that observed in paired wild-type mice. Capsaicin (which releases endogenous neuropeptides) and exogenous tachykinins induced edema formation, which was reduced by the mast cell amine histamine H(1) antagonist mepyramine (P < 0.05). These findings confirm that tachykinins mediate edema formation via the NK(1) receptor and provide direct evidence that the septide-sensitive binding site is on the NK(1) receptor. Furthermore, results suggest that edema induced by the tachykinins, although totally dependent on NK(1) receptor-mediated mechanism, contains a mast cell-dependent component. The evidence is in keeping with an NK(1) receptor on mast cells.
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Pharmacology Group and Vascular Biology Research Centre, School of Biomedical Sciences, King's College, London SW3 6LX, United Kingdom.
Gerard
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Brain
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D000818:Animals; D002211:Capsaicin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced* / Q000188:drug therapy; D005260:Female; D006634:Histamine H1 Antagonists / Q000627:therapeutic use; D007271:Injections, Intradermal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D011738:Pyrilamine / Q000627:therapeutic use; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D012871:Skin Diseases / Q000139:chemically induced* / Q000188:drug therapy; D013373:Substance P / Q000008:administration & dosage; D015320:Tachykinins / Q000008:administration & dosage; D003189:p-Methoxy-N-methylphenethylamine / Q000008:administration & dosage
D006634:Histamine H1 Antagonists; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; D013373:Substance P; D003189:p-Methoxy-N-methylphenethylamine; D011738:Pyrilamine; D002211:Capsaicin