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)

Bradford D. Fischer, Laurence L Miller, Fredrick E. Henry, Mitchell J. Picker, Linda A. Dykstra

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)271-278
Number of pages8
JournalPsychopharmacology
Volume198
Issue number2
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

Fingerprint

LY 235959
Excitatory Amino Acid Antagonists
Buprenorphine
Metabotropic Glutamate Receptors
Carboxylic Acids
Inbred C57BL Mouse
Opioid Analgesics
LY 341495
N-Methyl-D-Aspartate Receptors
Opioid Receptors
Pharmaceutical Preparations
Morphine
dezocine

Keywords

  • Antinociception
  • Efficacy
  • Glutamate
  • Metabotropic
  • NMDA
  • Opioid

ASJC Scopus subject areas

  • Pharmacology

Cite this

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). / Fischer, Bradford D.; Miller, Laurence L; Henry, Fredrick E.; Picker, Mitchell J.; Dykstra, Linda A.

In: Psychopharmacology, Vol. 198, No. 2, 01.06.2008, p. 271-278.

Research output: Contribution to journalArticle

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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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AU - Miller, Laurence L

AU - Henry, Fredrick E.

AU - Picker, Mitchell J.

AU - Dykstra, Linda A.

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N2 - 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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