Use of NK1 knockout mice to analyze substance P-induced edema formation.

The mechanisms involved in tachykinin-induced neurokinin-1 (NK1) receptor-mediated edema formation have been studied in anesthetized wild-type and NK1 knockout mice. Intradermally injected substance P (30-300 pmol), NK1 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 injected125I-labeled albumin. Septide was 3-10× 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 H1 antagonist mepyramine ( P < 0.05). These findings confirm that tachykinins mediate edema formation via the NK1 receptor and provide direct evidence that the septide-sensitive binding site is on the NK1 receptor. Furthermore, results suggest that edema induced by the tachykinins, although totally dependent on NK1 receptor-mediated mechanism, contains a mast cell-dependent component. The evidence is in keeping with an NK1 receptor on mast cells.