Tachykinin NK₁ receptor antagonist RP67580 attenuates progressive hypersensitivity of flexor reflex during experimental inflammation in rats

We have now examined whether the tachykinin NK₁ receptor is involved in mediating progressive hypersensitivity of spinal flexor motoneurons induced by repeated peripheral stimulation of inflamed tissue in decerebrate-spinal rats. The mechanical threshold of spinal flexor motoneurons was significantly decreased, and the touch- and pinch-evoked responses significantly increased, 48 h after intra-plantar injection of 100 μl complete Freund's adjuvant. The threshold was further progressively decreased and the touch- and pinch-evoked responses increased over the 80 min testing period. Subcutaneous injection of the tachykinin NK₁ receptor antagonist RP67580 (2-[1-imino-2-(2-methoxy phenyl) ethyl]-7,7 diphenyl-4 perhydroisoindolone-(3aR,7aR)) (20 min prior to the beginning of the test) at 1 mg and 10 mg/kg significantly attenuated the progressive decrease of mechanical withdrawal threshold, and the progressive increase of the touch- and pinch-evoked responses. The inactive enantiomer RP68651 (2-[1-imino-2-(2-methoxy phenyl) ethyl]-7,7 diphenyl-4 perhydroisoindolone-(3aS,7aS)) at 1 mg and 10 mg/kg had no significant effect. The present results indicate that substance P and its preferred tachykinin NK₁ receptor are involved in mediating progressive hypersensitivity during inflammation.