The neurokinin-1 receptor antagonist RP 67580 reduces the sensitization ofprimary afferents by substance P in the rat

The inflammatory mediator substance P (SP) produces a variety of biological effects in several tissues by binding to the tachyldnin receptor neurokini n 1 (NK1) and, to a lesser extent, by binding to the neurokinin 2 receptor (NK2). To assess the sensitizing effect of SP on articular afferent fibres the NK1 receptor antagonist RP 67580 was applied in normal and acutely infl amed rat knee joints. Altogether 38 fine afferent nerve Fibres from the rat knee with conduction velocities of 0.71-13.5 m/s were recorded as single units, during non-noxio us and noxious joint rotations. SP, injected i.a. as a bolus close to the k nee joint, was able to sensitize 45.5% (10 of 22) of the units recorded fro m normal joints and 33.3% (five of 15) of afferents from inflamed joints. T he following i.a. application of RP 67580 in a range of 20 200 nmol antagon ized in a dose-dependent manner the sensitizing effect of SP in a large pro portion of slowly conducting articular afferents from normal (66.7%) and in flamed (46.2%) knee joints. Subsequent SP application enhanced the afferent sensitivity further. The electrophysiological results presented here furth er support the suggestion that the sensitization of afferents by SP in the rat knee joint is mediated mainly by the NK, receptor, which is probably lo cated on the primary afferents. (C) 2001 European Federation of Chapters of the International Association for the Study of Pain.