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 μ-opioid receptor agonists buprenorphine and dezocine were first assessed in a hot-plate procedure under conditions of low (53°C) and high (56°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°C and produced submaximal antinociceptive effects at 56°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°C, as revealed by significant increases in the peak effects of both drugs to ~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.
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Acknowledgments
This study was supported by US Public Health Service grants R01-DA02749, T32-DA07244, and F31-DA022788.
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Fischer, B.D., Miller, L.L., Henry, F.E. et al. Increased efficacy of μ-opioid agonist-induced antinociception by metabotropic glutamate receptor antagonists in C57BL/6 mice: comparison with (−)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959). Psychopharmacology 198, 271–278 (2008). https://doi.org/10.1007/s00213-008-1130-y
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DOI: https://doi.org/10.1007/s00213-008-1130-y