Effect of RP 67580, a non-peptide neurokinin1 receptor antagonist, on facilitation of a nociceptive spinal flexion reflex in the rat

Abstract

1. In order to examine the contribution of neurokinin1 (NK1) receptors to facilitation of a spinal nociceptive reflex in the rat, we have investigated the effects of RP 67580 (3aR, 7aR)-7,7-diphenyl-2(1-imino-2-(2-methoxyphenyl/ethyl)perhydrois oindole)), a non-peptide neurokinin1 (NK1) receptor antagonist, selective for the rodent receptor sub-type, on the activity of individual motorunits. These results were compared with the effects of RP 68651, the inactive 3aS, 7aS enantiomer of RP 67580, as a control for non-specific activity. 2. Experiments were performed on 15 rats anaesthetized with a continuous i.v. infusion of alphaxalone/alphadalone and spinalized at T9-10. Single unit recordings of motorunit activity from biceps femoris/semitendinosus were made with a concentric needle electrode. In each experiment, a vehicle dose followed by 4 sequential rising doses of either RP 67580 or RP 68651 were given at 15 min intervals. High intensity electrical stimuli were applied to the hindlimb receptive field of the motorunit at a rate of 1 per 60 s throughout the experiment to establish a baseline. A conditioning stimulus (20 of these stimuli at 1 Hz) was delivered 5 min after each dose and the effect of the size of the baseline response examined. 3. The conditioning stimulus evoked a facilitation of the baseline at the start of all experiments (mean increase +/- s.e. mean = 151 +/- 20%). RP 67580 attenuated this facilitation, with an ID50 (+/- s.e. mean) of 2.5 +/- 4.2 micrograms kg-1, i.v., whereas RP 68651 at doses of up to 3 mg kg-1, i.v. did not. There was no statistically significant effect of drug on the baseline reflex, nor on the response to the conditioning stimulus. Doses of 300 and 3000 microg kg-1 of both RP 67580 and RP 68651 evoked small depressor effects on systemic arterial blood pressure.4. We conclude that the facilitation of a spinal flexor reflex by noxious conditioning stimuli in the rat is mediated by NK1 receptors whereas the baseline reflex is not. The results suggest that brain penetrantNK1 receptor antagonists may have central anti-nociceptive effects.