Different effects of NMDA/group I metabotropic glutamate receptor agents in δ- and μ-opioid receptor agonist-induced supraspinal antinociception

doi:10.1016/S0014-2999(00)00183-7

European Journal of Pharmacology

Volume 396, Issue 1, 12 May 2000, Pages 23-28

https://doi.org/10.1016/S0014-2999(00)00183-7 Get rights and content

Abstract

The N-methyl-d-aspartate (NMDA) and metabotropic glutamate (mGlu) receptors are involved in nociceptive transmission in the central nervous system. The present study was designed to study the effects of NMDA and group I mGlu receptor agents on δ- and μ-opioid receptor agonist-induced antinociception in the mouse brain. Intracerebroventricular (i.c.v.) treatment with the non-competitive NMDA receptor antagonist dizocilpine and the group I mGlu receptor antagonist (S)-4-carboxyphenylglycine ((S)-4CPG) significantly attenuated the antinociception induced by the δ-opioid receptor agonists [d-Pen², Pen⁵]enkephalin (DPDPE), (−)-TAN 67 and [d-Ala²]deltorphin II. On the contrary, i.c.v. administration of dizocilpine and (S)-4CPG slightly but significantly enhanced the antinociception induced by the μ-opioid receptor agonist [d-Ala², N-Me-Phe⁴, Gly⁵-ol]enkephalin (DAMGO). Under these conditions, i.c.v. administration of NMDA and the group I mGlu receptor agonist 3,5-dihydrophenylglycine (DHPG) significantly enhanced the antinociception induced by δ-opioid receptor agonists, whereas both reduced DAMGO-induced antinociception. These findings suggest that the supraspinal antinociceptive actions of μ- and δ-opioid receptor agonists appear to be modulated differently by NMDA and group I mGlu receptors in the mouse.

Introduction

Opioid drugs produce their actions by interacting with at least three types of opioid receptors; μ, κ and δ. In recent years, several studies have been undertaken to determine the potential role of excitatory amino acids in the antinociceptive responses to opioid drugs in mice and rats. Clinically, to obtain complete analgesia, a combination of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine and an opioid agonist is a very powerful approach when the pain cannot be controlled by morphine alone Oshima et al., 1990, Yang et al., 1996, Rabben et al., 1999.

Glutamate is a major transmitter in central pain pathways. The excitatory effect of glutamate is mediated by ionotropic (NMDA and α-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) types) and metabotropic receptors. NMDA receptors consist of multiple subunits that regulate transmembrane ion flux, whereas metabotropic glutamate (mGlu) receptors contain seven transmembrane domain proteins that couple to intracellular second messenger systems through G-proteins Sugiyama et al., 1987, Nakanishi, 1992, Hayashi et al., 1994, Hollmann and Heinemann, 1994. Recently, molecular cloning and pharmacological studies have revealed the existence of at least eight mGlu receptor subtypes (mGlu₁ receptor–mGlu₈ receptor). The mGlu₁ receptor and mGlu₅ receptor, which are classified as group I, are positively coupled to the phosphatidylinositol-phospholipase C system, whereas the others are negatively coupled to adenylate cyclase. The mGlu₂ receptor and mGlu₃ receptor are classified as group II, while mGlu₄ receptor, mGlu₆ receptor, mGlu₇ receptor and mGlu₈ receptor are classified as group III.

NMDA and group I mGlu receptors are both located in postsynaptic elements Martin et al., 1992, Shigemoto et al., 1993. Opioid receptors and glutamate (NMDA, mGlu) receptors have been shown to be similarly distributed in the brain Masu et al., 1994, Mansour et al., 1995, suggesting that some of these receptors may control nociceptive neurotransmission through a physiological balance in the same plasma membrane site. Thus, it is possible that opioid receptors and group I mGlu receptors share common pools of intracellular second messengers. However, little is known about the effects of direct interaction, if any, between μ- or δ-opioid and glutamate receptors on antinociceptive responses.

The present study was designed to investigate the effects of the pharmacological interaction of NMDA or group I mGlu receptor agents on the antinociception induced by the i.c.v. administration of a δ- or μ-opioid receptor agonist in mice.

Section snippets

Materials and methods

The present study was conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals, Hoshi University, as adopted by the Committee on Animal Research of Hoshi University, which is accredited by the Ministry of Education, Science, Sports and Culture of Japan.

Results

Both selective δ- and μ-opioid receptor agonists produced maximal antinociceptive responses at 10 min after these drugs were given i.c.v. (data not shown). The glutamate receptor agents, dizocilpine (0.03–3.0 nmol/mouse), NMDA (10 and 30 pmol/mouse), (S)-4CPG (10–56 nmol/mouse) and DHPG (3.0–10 nmol/mouse), were co-administered with δ-opioid receptor agonists. When administered i.c.v. at the doses used in the present study, none of glutamate receptor agents produced any change of the warm-plate

Discussion

The present results show that the NMDA receptor antagonist dizocilpine given i.c.v. reduces the supraspinal antinociception induced by δ-opioid agonists such as DPDPE, (−)-TAN 67 and [d-Ala²]deltorphin II in the mouse warm-plate test. These findings are consistent with the finding that intraperitoneal (i.p.) pretreatment with competitive ([3S-(3α,4aα,6β,8aα)]-decahydro-6-(phosphonomethyl)-3-isoquinolinecarboxylic acid; LY 235959) and non-competitive antagonists (dizocilpine; MK-801) of NMDA

Acknowledgements

This work was supported in part by grants from the Ministry of Health and Welfare, and the Ministry of Education, Science, Sports and Culture of Japan to T. Suzuki. We wish to thank Ms. Aya Myoga for her expert technical assistance.

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Different effects of NMDA/group I metabotropic glutamate receptor agents in δ- and μ-opioid receptor agonist-induced supraspinal antinociception

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

J. Biol. Chem.

Jpn. J. Pharmacol.

Trends Neurosci.

Neuron

FEBS Lett.

Neuropharmacology

Trends Pharmacol. Sci.

Neurosci. Lett.

Effects of competitive and noncompetitive antagonists of N-methyl-d-aspartate receptor on the analgesic action of δ1- and δ2-opioid agonists in mice

Br. J. Pharmacol.

Pharmacological effects produced by intracerebral injections of drugs in the conscious mouse

Br. J. Pharmacol.

Analysis of agonist and antagonist activities of phenylglycine derivatives for different cloned metabotropic glutamate receptor subtypes

J. Neurosci.

Ca2+ agonists and antagonists of the dihydropyridine type: antinociceptive effects, interference with opiate μ-receptor agonists and neuropharmacological actions in rodents

Psychopharmacology

Effects of competitive and noncompetitive antagonists of N-methyl-d-aspartate receptor on the analgesic action of δ₁- and δ₂-opioid agonists in mice

Ca²⁺ agonists and antagonists of the dihydropyridine type: antinociceptive effects, interference with opiate μ-receptor agonists and neuropharmacological actions in rodents