Metabotropic and NMDA glutamate receptors participate in the cannabinoid-induced antinociception

The purpose of this study was to evaluate the possible contribution of meta botropic glutamate receptors (mGluRs) to cannabinoid-induced antinociceptio n in the periaqueductal grey (PAG) matter of rats. Intra-PAG microinjection of WIN 55,212-2, a cannabinoid receptor agonist, increased the latency of the nociceptive reaction (NR) in a dose-dependent fashion in the plantar te st. This effect was prevented by pretreatment with SR141716A, a selective a ntagonist of CB1 receptors. When injected alone, SR141716A produced, with t he highest dosage used, a significant reduction in the latency of the NR. C PCCOEt, a selective mGlu1 receptor antagonist, was unable to prevent the an algesia produced by WIN 55,212-2. On the contrary, MPEP, a selective mGlu5 receptor antagonist, completely antagonized the effect of WIN 55,212-2. How ever, the analgesia induced by CHPG, a selective mGlu5 receptor agonist, wa s blocked by MPEP but not by SR141716A. When injected alone, CPCOOEt produc ed no effect, whereas MPEP produced, with the highest dosage used, a signif icant reduction in the latency of the NR. These data emphasize that mGlu5 r eceptors. but not mGluR1, may modulate nociception in the PAG. Similarly, a pretreatment with either 2-(S)-alpha -EGlu or (RS)-alpha- MSOP, selective antagonists for group LT and III mGluRs, respectively, prevented the WIN 55 ,212-2-induced analgesia. When the higher dosage of (RS)-alpha -MSOP was us ed a decrease in the latency of the NR was observed. This was not the case for 2-(S)-alpha -EGlu. Pretreatment with DL-APS, a selective antagonist of N-methyl-D-aspartate (NMDA) receptors, blocked the effect of WIN 55,212-2, and by increasing the dosage strongly reduced per se the latency of the NR. This study suggests that endogenous glutamate could tonically modulate noc iception through mGlu and NMDA receptors in the PAG matter. In particular, the physiological stimulation of these receptors seems to be required for t he cannabinoid-induced analgesia in this midbrain area. (C) 2001 Elsevier S cience Ltd. All rights reserved.