Different effects of NMDA/group I metabotropic glutamate receptor agents in δ- and μ-opioid receptor agonist-induced supraspinal antinociception
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.
References (24)
- et al.
Pertussis toxin inhibits enkephalin stimulation of GTPase of NG108-15 cell
J. Biol. Chem.
(1983) - et al.
Significance of Ca2+ ion in the morphine analgesia
Jpn. J. Pharmacol.
(1964) - et al.
Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications
Trends Neurosci.
(1995) - et al.
Cellular localization of a metabotropic glutamate receptor in the rat brain
Neuron
(1992) - et al.
δ-Opioid receptor mediates phospholipase C activation via Gi in Xenopus oocytes
FEBS Lett.
(1993) - et al.
The metabotropic glutamate receptors: structure and functions
Neuropharmacology
(1995) - et al.
Metabotropic glutamate receptors in brain function and pathology
Trends Pharmacol. Sci.
(1993) - et al.
Immunohistochemical localization of a metabotropic glutamate receptor, mGluR 5, in the rat brain
Neurosci. Lett.
(1993) - et al.
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.
(1996) - et al.
Pharmacological effects produced by intracerebral injections of drugs in the conscious mouse
Br. J. Pharmacol.
(1957)
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
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