Modulation of nociceptive transmission by NMDA/glycine site receptor in the ventroposterolateral nucleus of the thalamus

Abstract NMDA-type glutamate receptors are involved in the generation and maintenance of altered pain states. In the present study, we examined the effect of an NMDA-glycine site antagonist, GV196771A [E-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1 H -indole-2-carboxylic acid sodium salt], on responses to noxious stimuli both in normal rats and during peripheral mononeuropathy induced by chronic constriction injury (CCI) of the sciatic nerve. In one series of experiments, activity of nociceptive neurons in the ventroposterolateral (VPL) nucleus of the thalamus was recorded in response to pressure stimuli to the contralateral hindpaw. Intravenous injection (iv) of the glycine antagonist had no effect on these cells in normal rats. When tested in rats with CCI induced 2–3 weeks previously, however, GV196771A (0.125, 0.5 and 2.0 mg/kg) blocked responses to noxious stimulation in a dose-dependent and reversible manner. Morphine (0.5 mg/kg, iv) and the NMDA channel blocker MK801 (0.1 mg/kg, iv) suppressed noxious stimulus-evoked activity of VPL neurons in both normal and CCI-treated rats. MK801 also decreased the responses of non-nociceptive neurons to brush stimulation in both sets of animals, in contrast to the glycine antagonist which did not alter the responses of these cells. Similar results were obtained from a series of behavior experiments in which the latency for paw withdrawal from heat stimulation was measured in normal and CCI-treated rats. GV196771A (3 and 10 mg/kg) injected orally, reduced the hyperalgesic response in the treated rats but did not change the withdrawal latency in normal rats. Taken together, these findings suggest that block of the NMDA receptor decreases nociceptive transmission in the thalamus and can modulate hyperalgesic states. GV196771A and glycine antagonists in general may represent innovative and safe agents for the treatment of neuropathic pain.