Potent antihyperalgesic activity without tolerance produced by glycine site antagonist of N-methyl-D-aspartate receptor GV196771A

Central sensitization is a condition of enhanced excitability of spinal cor d neurons that contributes to the exaggerated pain sensation associated wit h chronic tissue or nerve injury. N-methyl-D-aspartate (NMDA) receptors are thought to play a key role in central sensitization. We have tested this h ypothesis by characterizing in vitro and in vivo a novel antagonist of the NMDA receptor acting on its glycine site, GV196771A. GV196771A exhibited an elevated affinity for the NMDA glycine binding site in rat cerebral cortex membranes (pK(i) = 7.56). Moreover, GV196771A competitively and potently a ntagonized the activation of NMDA receptors produced by glycine in the pres ence of NMDA in primary cultures of cortical, spinal, and hippocampal neuro ns (pK(B) = 7.46, 8.04, and 7.86, respectively). In isolated baby rat spina l cords, 10 mu M GV196771A depressed wind-up, an electrical correlate of ce ntral sensitization. The antihyperalgesic properties of GV196771A were stud ied in a model of chronic constriction injury (CCI) of the rat sciatic nerv e and in the mice formalin test. In the CCI model GV196771A (3 mg/kg twice a day p.o.), administered before and then for 10 days after nerve ligature, blocked the development of thermal hyperalgesia. Moreover, GV196771A (1-10 mg/kg p.o.) reversed the hyperalgesia when tested after the establishment of the CCI-induced hyperalgesia. In the formalin test GV196771A (0.1-10 mg/ kg p.o.) dose-dependently reduced the duration of the licking time of the l ate phase. These antihyperalgesic properties were not accompanied by develo pment of tolerance. These observations strengthen the view that NMDA recept ors play a key role in the events underlying plastic phenomena, including h yperalgesia. Moreover, antagonists of the NMDA glycine site receptor could represent a new analgesic class, effective in conditions not sensitive to c lassical opioids.