EFFECT OF RP 67580, A NONPEPTIDE NEUROKININ(1) RECEPTOR ANTAGONIST, ON FACILITATION OF A NOCICEPTIVE SPINAL FLEXION REFLEX IN THE RAT

1 In order to examine the contribution of neurokinin1 (NK1) receptors to facilitation of a spinal nociceptive reflex in the rat, we have inv estigated the effects of RP 67580 mino-2-(2-methoxyphenyl/ethyl)perhyd roisoindole)), a non-peptide neurokinin1 (NK1) receptor antagonist, se lective for the rodent receptor sub-type, on the activity of individua l motorunits. These results were compared with the effects of RP 68651 , the inactive 3aS, 7aS enantiomer of RP 67580, as a control for non-s pecific activity. 2 Experiments were performed on 15 rats anaesthetize d with a continuous i.v. infusion of alphaxalone/alphadalone and spina lized at T9-10. Single unit recordings of motorunit activity from bice ps femoris/semitendinosus were made with a concentric needle electrode . In each experiment, a vehicle dose followed by 4 sequential rising d oses of either RP 67580 or RP 68651 were given at 15 min intervals. Hi gh intensity electrical stimuli were applied to the hindlimb receptive field of the motorunit at a rate of 1 per 60 s throughout the experim ent to establish a baseline. A conditioning stimulus (20 of these stim uli 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 e voked a facilitation of the baseline at the start of all experiments ( mean increase +/- s.e.mean = 151 +/- 20%). RP 67580 attenuated this fa cilitation, with an ID50 (+/- s.e.mean) of 2.5 +/- 4.2 mug 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, n or on the response to the conditioning stimulus. Doses of 300 and 3000 mug kg-1 of both RP 67580 and RP 68651 evoked small depressor effects on systemic arterial blood pressure. 4 We conclude that the facilitat ion of a spinal flexor reflex by noxious conditioning stimuli in the r at is mediated by NK1 receptors whereas the baseline reflex is not. Th e results suggest that brain penetrant NK1 receptor antagonists may ha ve central anti-nociceptive effects.