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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 Mice¹

Thong Cao^*, Erika Pintér^*, Sabah Al-Rashed^*, Norma Gerard, J. Robin Hoult and Susan D. Brain^2,*

^* Centre for Cardiovascular Biology and Medicine and Messengers and Signaling Group, King’s College London, London, United Kingdom; and Perlmutter Laboratory, Children’s Hospital, Boston, MA 02115

We have used tachykinin neurokinin-1 receptor (NK₁ receptor) knockout mice to learn of the link between NK₁ receptors and neutrophil accumulation in normal naive skin, as compared with inflamed skin. Intradermal substance P (300 pmol) induced edema formation in wild-type mice, but not in NK₁ knockout mice, as expected. However, in contrast to IL-1ß (0.3 pmol), substance P did not induce neutrophil accumulation in wild-type mice. IL-1ß-induced neutrophil accumulation was similar in wild-type and knockout mice, but a significant (p < 0.05) contributory effect of added NK₁ agonists, which by themselves have no effect on neutrophil accumulation in normal skin, was observed. The results support the concept that NK₁ agonists such as substance P cannot act on their own to mediate neutrophil accumulation in naive skin and provide direct evidence that in inflamed skin, under certain circumstances, the NK₁ receptor can play a pivotal role in modulating neutrophil accumulation during the ongoing inflammatory process. We investigated responses to two inflammatory stimuli (carrageenin and zymosan). Neutrophil accumulation was significantly attenuated (p < 0.001) in carrageenin- but not zymosan-induced inflammation in NK₁ knockout mice. The carrageenin (500 µg)-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 bradykinin B₁ and B₂ receptor antagonists (desArg⁹[Leu⁸]bradykinin and HOE 140) 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 participate in NK₁ receptor-dependent neutrophil accumulation in inflamed mouse skin.

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