The neurokinin-1 receptor antagonist RP 67580 reduces the sensitization of primary 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 tachykinin receptor neurokinin 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 NK1receptor antagonist RP 67580 was applied in normal and acutely inflamed 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-noxious and noxious joint rotations. SP, injected i.a. as a bolus close to the knee joint, was able to sensitize 45.5% (10 of 22) of the units recorded from normal joints and 33.3% (five of 15) of afferents from inflamed joints. The following i.a. application of RP 67580 in a range of 20-200 nmol antagonized in a dose-dependent manner the sensitizing effect of SP in a large proportion of slowly conducting articular afferents from normal (66.7%) and inflamed (46.2%) knee joints. Subsequent SP application enhanced the afferent sensitivity further. The electrophysiological results presented here further support the suggestion that the sensitization of afferents by SP in the rat knee joint is mediated mainly by the NK1 receptor, which is probably located on the primary afferents. Copyright 2001 European Federation of Chapters of the International Association for the Study of Pain.