Cold-freeze injury at -4 degrees C to the rat sciatic nerve produces mechanical allodynia and thermal hyperalgesia [M.A. Kleive, P.S. Jungbluth, J.A. Uhlenkamp, K.C. Kajander, Cold injury to rat sciatic nerve induces thermal hyperalgesia or analgesia, 8th World Congress on Pain, Vancouver, BC, Canada, August 1996 (Abstract).]. The NMDA receptor, an excitatory amino acid (EAA) receptor, appears to be involved in the development of allodynia and hyperalgesia following nerve injury. The role, if any, of the kainate receptor, another EAA receptor, remains unknown. In the current study, we evaluated whether (2S,4R)-4-methylglutamic acid (SYM-2081), a recently developed kainate receptor antagonist, attenuates increased responsiveness following cold injury to the sciatic nerve. During baseline testing, Sprague-Dawley rats were evaluated for frequency of withdrawal from von Frey filaments and latency of withdrawal from a radiant thermal source. Animals were then anesthetized, the left sciatic nerve was exposed, and the nerve was cooled to -4 degrees C for 15 min (n=24). For control rats (n=24), all procedures were identical except that the nerve was maintained at 37 degrees C. Testing resumed on the third day following surgery. On the fifth post-operative day, SYM-2081 (150 or 100 mg/kg), fentanyl citrate (0. 04 mg/kg) or vehicle was injected intraperitoneally. Injury to the rat sciatic nerve induced a significant increase in withdrawal frequency and a significant decrease in withdrawal latency (ANOVA, p<0.05). SYM-2081 and fentanyl significantly reduced these responses (p<0.05). These results suggest that kainate and opioid receptors are involved in the mechanical allodynia and thermal hyperalgesia that develop following cold injury to the sciatic nerve.