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)

• Published in: Psychopharmacologia Vol. 198; no. 2; pp. 271 - 278
• Main Authors: Fischer, Bradford D., Miller, Laurence L., Henry, Fredrick E., Picker, Mitchell J., Dykstra, Linda A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-06-2008; Springer
• Subjects: Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Medical sciences; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry; NMDA; Opioid; Metabotropic; Efficacy; Antinociception; Glutamate; Agonist; Rodentia; Opiates; Glutamate receptor; Opioid peptide; Analgesia; Vertebrata; Mammalia; Metabotropic receptor; Mouse; Efficiency; Animal; Excitatory aminoacid; Neurotransmitter; Antagonist; Comparative study
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-008-1130-y

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.