Neurokinin-1 receptor agonists are involved in mediating neutrophil accumulation in the inflamed, but not normal, cutaneous microvasculature: An in vivo study using neurokinin-1 receptor knockout mice

We have used tachykinin neurokinin-1 receptor (NK1 receptor) knockout mice to learn of the link between NK1 receptors and neutrophil accumulation in n ormal naive skin, as compared with inflamed skin. Intradermal substance P ( 300 pmol) induced edema formation in wild-type mice, but not in NK1 knockou t mice, as expected. However, in contrast to IL-1 beta (0.3 pmol), substanc e P did not induce neutrophil accumulation in wild-type mice. IL-1 beta-ind uced neutrophil accumulation was similar in wild-type and knockout mice, bu t a significant (p < 0.05) contributory effect of added NK1 agonists, which by themselves have no effect on neutrophil accumulation in normal skin, wa s observed. The results support the concept that NK1 agonists such as subst ance P cannot act on their own to mediate neutrophil accumulation in naive skin and provide direct evidence that in inflamed skin, under certain circu mstances, the NK1 receptor can play a pivotal role in modulating neutrophil accumulation during the ongoing inflammatory process. We investigated resp onses to two inflammatory stimuli (carrageenin and zymosan), Neutrophil acc umulation was significantly attenuated (p < 0.001) in carrageenin- but not zymosan-induced inflammation in NK1 knockout mice. The carrageenin (500 mu g)-induced response was inhibited (p < 0.05) by a NK1 receptor antagonist, SR140333 (480 nmol/kg i.v. at -5 min), in the wild-type group. The bradykin in B-1 and B-2 receptor antagonists (desArg(9)[Leu(8)]bradykinin and HOE 14 0) each reduced neutrophil accumulation to carrageenin in wild-type animals (p < 0.05), but did not cause further reduction of the suppressed response of knockout mice. The results provide evidence that kinin receptors partic ipate in NK1 receptor-dependent neutrophil accumulation in inflamed mouse s kin.