Substance P‐induced inflammatory responses in guinea‐pig skin: The effect of specific NK₁ receptor antagonists and the role of endogenous mediators

Abstract

1 The sensory neuropeptide substance P (SP), when released from sensory nerves, has been implicated in the development of neurogenic inflammation. In the present study, using an in vivo model system, we have characterized and investigated the mechanisms underlying SP‐induced leukocyte accumulation and oedema formation in the guinea‐pig. 2 Intradermaly injected SP (i.d., 10 −13 ‐10 −9 mol per site), induced a dose‐ and time‐dependent accumulation of 111 In‐neutrophils, 111 In‐eosinophils and oedema formation as measured by the local accumulation of i.v. injected l25 I‐albumin. The leukocyte accumulation evoked by SP was significant at 10 −10 and 10 −9 mol per site, whereas oedema formation was significant at the lowest dose tested (10 −13 mol per site). 3 The NK 1 receptor antagonists, CP‐96,345 (1 mgkg −1 , i.v.) and RP‐67,580 (10 μg per site, i.d.), significantly attenuated the oedema formation induced by the lower doses of SP. Oedema formation and leukocyte accumulation induced by 10 −9 mol per site SP were unaffected by either antagonist. 4 SP‐elicited responses were not significantly affected by the platelet activating factor (PAF) receptor antagonist, UK‐74,505 (2.5 mgkg −1 , i.v.) or the H 1 histamine receptor antagonist, chlorpheniramine (10 −8 mol per site, i.d.). However, the 111 In‐eosinophil accumulation, but not the 111 In‐neutrophil accumulation or oedema formation, induced by SP was significantly inhibited by the specific 5lipoxygenase (5‐LO) inhibitor, ZM‐230,487 (10 −8 mol per site, i.d.). 5 The accumulation of both 111 In‐neutrophils and 111 In‐eosinophils induced by SP was abolished in guinea‐pigs treated i.v. with an anti‐CD 18 monoclonal antibody 6.5E F(ab′) 2 (2.5 mgkg −1 ). The oedema response was unaffected in these animals. 6 These results suggest that SP‐induced inflammatory events may be mediated via two mechanisms involving NK 1 receptor‐dependent and independent pathways. Oedema formation induced by the lower doses of SP may be mediated via the direct activation of NK 1 receptors whilst, at higher doses, oedema formation and leukocyte accumulation may be mediated via the release of secondary mediators, possibly mast cell derived, with 5‐LO products playing an important role in the leukocyte infiltration. The leukocyte accumulation, but not the oedema induced by SP, is dependent on the expression of the CD 18 antigen on leukocytes.