The kainate receptor antagonist 2S, 4R-4-methylglutamate attenuates mechanical allodynia and thermal hyperalgesia in a rat model of nerve injury

Opioids and receptor antagonists of excitatory amino acids attenuate mechanical allodynia and thermal hyperalgesia in animal models of neuropathic pain. Recently, a kainate receptor antagonist, 2S,4R-4-methylglutamate, has been developed but has not been tested for antinociceptive effects in animal models of neuropathic pain. We evaluated whether 2S,4R-4-methylglutamate attenuated responses to mechanical and thermal stimuli in uninjured (control) rats and increased responsiveness in rats with chronic constriction injury. Rats were tested for a number of withdrawal responses using a calibrated von Frey filament (mechanical stimulus) and withdrawal latencies from a radiant heat source (thermal stimulus). In control rats, 2S,4R-4-methylglutamate produced a small but significant decrease in responses from the mechanical stimulus (25 mg/kg) and significantly increased withdrawal latencies from the thermal stimulus at the highest dose administered (100 mg/kg). In addition, 2S,4R-4-methylglutamate greatly attenuated increased responsiveness in rats with chronic constriction injury. At four to eight days following chronic constriction injury, animals that displayed increased responsiveness to mechanical and thermal stimuli were injected intraperitoneally with either dizocilpine maleate (0.1 mg/kg), morphine (4 mg/kg), vehicle as controls, or 2S,4R-4-methylglutamate (25, 50, 75 or 100 mg/kg). 2S,4R-4-Methylglutamate (25, 50, 75 and 100 mg/kg) significantly attenuated the frequency of responses to mechanical stimuli (Wilcoxon, P < 0.05) and the latency of responses to thermal stimuli (analysis of variance and Duncan's, P < 0.05). Dizocilpine maleate and morphine, as expected, also reduced these responses. These results suggest that, in addition to opioid and N-methyl-D-aspartate receptors, kainate receptors may play a role in the maintenance of mechanical allodynia and thermal hyperalgesia associated with peripheral nerve injury.