Receptor subtypes involved in tachykinin-mediated edema formation

Intradermal (ID) injection of the natural tachykinins substance P (SP), neu rokinin A (NKA), and neurokinin B (NKB) (0.3-30 nmol) resulted in a marked and dose-related rat paw edema, with mean ED50 values of 2.68 nmol, 1.17 nm ol, and 0.80 nmol, respectively. The ID injection of the selective NK1, SP methyl-ester (1-30 nmol), NK2, [beta-Ala(8)]-neurokinin A(4-10) (beta-Ala, 0.3-30 nmol). or NK3, senktide (1-10 nmol) agonists, caused extensive edema formation with mean ED(50)s of 0.48 nmol, 0.41 nmol, and 0.18 nmol, respec tively. The ID injection of the selective NK1 antagonist FK888 (0.1-3 nmol) produced marked inhibition (94%. 52%, and 66%, respectively) of rat paw ed ema induced by SP, NKA, or SP methyl-eater. The ID co-injection of the NK2 receptor antagonist SR 48968 elicited a graded inhibition (52%, 67%, and 35 %, respectively) of rat paw edema induced by NKA, beta-Ala and, to a lesser extent, the edema caused by SP. Finally, the ID co-injection of the NK3 re ceptor antagonist SR 142801 significantly inhibited (53%. 76%, 53%, and 100 %, respectively) the edema formation caused by NKB and NKA or by SP and sen ktide. Together, the data of the present study suggest that tachykinin-medi ated rat paw edema depends on the activation of NK1, NK2 and NK3 receptor s ubtypes, with apparent major involvement of NK1 receptors subtypes. (C) 199 9 Elsevier Science Inc. All ri hts reserved.