Increased efficacy of micro-opioid agonist-induced antinociception by metabotropic glutamate receptor antagonists in C57BL/6 mice: comparison with (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959)

Abstract

Rationale: Recent experimental data suggest that metabotropic glutamate receptor (mGluR) antagonists with selectivity for mGluR1 and mGluR2/3 enhance morphine-induced antinociception.

Objectives: The present study addressed the hypothesis that mGluR antagonists enhance opioid antinociception by increasing opioid efficacy.

Materials and methods: The antinociceptive effects of the partial mu-opioid receptor agonists buprenorphine and dezocine were first assessed in a hot-plate procedure under conditions of low (53 degrees C) and high (56 degrees C) stimulus intensity. Under conditions in which buprenorphine and dezocine produced submaximal antinociceptive effects, these drugs were assessed after pretreatment with the mGluR1 antagonist JNJ16259685, the mGluR5 antagonist MPEP, the mGluR2/3 antagonist LY341495, and for comparison, the N-methyl-D-aspartate (NMDA) receptor antagonist LY235959.

Results: Buprenorphine (0.032-3.2 mg/kg) and dezocine (0.1-10 mg/kg) were fully efficacious at 53 degrees C and produced submaximal antinociceptive effects at 56 degrees C (i.e., their effects did not exceed 50% of the maximum possible effect). Pretreatment with JNJ16259685 (1.0-3.2 mg/kg), LY341495 (1.0-3.2 mg/kg), and LY235959 (0.32-1.0 mg/kg) enhanced the antinociceptive effects of buprenorphine and dezocine at 56 degrees C, as revealed by significant increases in the peak effects of both drugs to approximately 100% maximum possible effect. In contrast, pretreatment with MPEP (1.0-3.2 mg/kg) did not modulate the antinociceptive effects of buprenorphine and dezocine.

Conclusions: These results suggest that, similar to the NMDA receptor antagonist LY235959, the mGluR1 antagonist JNJ16259685 and the mGluR2/3 antagonist LY341495 increase the antinociceptive efficacy of buprenorphine and dezocine.