The purpose of this study was to evaluate the possible contribution of metabotropic
glutamate receptors (mGluRs) to cannabinoid-induced antinociception 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 test. This effect was prevented by pretreatment with SR141716A,
a selective antagonist of CB1 receptors. When injected alone, SR141716A produced,
with the highest dosage used, a significant reduction in the latency of the NR. CPCCOEt,
a selective mGlu1 receptor antagonist, was unable to prevent the analgesia produced
by WIN 55,212-2. On the contrary, MPEP, a selective mGlu5 receptor antagonist, completely
antagonized the effect of WIN 55,212-2. However, the analgesia induced by CHPG, a
selective mGlu5 receptor agonist, was blocked by MPEP but not by SR141716A. When injected
alone, CPCOOEt produced no effect, whereas MPEP produced, with the highest dosage
used, a significant reduction in the latency of the NR. These data emphasize that
mGlu5 receptors, 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 II and III mGluRs, respectively, prevented the WIN 55,212-2-induced analgesia.
When the higher dosage of (RS)-alpha-MSOP was used a decrease in the latency of the
NR was observed. This was not the case for 2-(S)-alpha-EGlu. Pretreatment with DL-AP5,
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
nociception through mGlu and NMDA receptors in the PAG matter. In particular, the
physiological stimulation of these receptors seems to be required for the cannabinoid-induced
analgesia in this midbrain area.