Full-length reviewNMDA and opioid receptors: their interactions in antinociception, tolerance and neuroplasticity
Introduction
Our understanding of interactions between the N-methyl-d-aspartate (NMDA) and opioid receptors has been advanced by a large number of studies carried out over the last several years. These studies provide valuable information concerning perhaps the two most important systems in nociception and antinociception: the NMDA and opioid receptor systems. In this review, focuses will be put on five major areas concerning interactions between the NMDA and opioid receptor systems. First, recent findings in the distribution of NMDA and opioid receptors within the central nervous system (CNS) will be briefly summarized. Second, interactions between these two systems will be examined with regard to their role in modulation of electrophysiological events mediated by NMDA receptor agonists and opioids. Third, the involvement of such interactions in antinociception, tolerance, dependence, and neuroplasticity will be considered. Emphasis will be given to the controversy regarding the role of NMDA receptors in functions mediated by distinct opioid receptor subtypes, namely μ, δ, and κ receptors. Fourth, intracellular events involving interactions between NMDA and opioid receptors will be discussed mainly within the scope of their role in tolerance and neuroplasticity. Finally, implications from such interactions in improving clinical pain management will be considered.
Section snippets
NMDA and opioid receptors: distributions within CNS
A combination of molecular biological, immunocytochemical, and autoradiographic receptor binding techniques has significantly enhanced our ability to examine the existence and distribution of NMDA and opioid receptors within the CNS. Such information, in turn, establishes a cellular basis for analyzing behavioral and electrophysiological evidence indicating interactions between the NMDA and opioid receptor systems. In particular, evidence for the modulation of NMDA and opioid receptor bindings
Modulation of NMDA receptor-mediated electrophysiological events by opioids
A considerable number of studies clearly indicate that opioids can directly modulate NMDA receptor-mediated electrophysiological events within the CNS (see below for details). There are three important features concerning such modulations. First, NMDA receptor-mediated electrophysiological events have been shown to be either inhibited or enhanced by opioids depending on preparations used in the experiments. Second, opioids appear to modulate differentially NMDA receptor-mediated
Role of NMDA receptors in opioid-mediated functions: behavioral evidence
A number of studies have shown multiple effects of NMDA receptor activation on opioid receptor-mediated functions such as antinociception, tolerance, dependence, and local motor activity. As discussed in the following sections, the involvement of NMDA receptor activation in these opioid-mediated functions appears to vary with the route of drug administration, opioid agonists used in the experiments, and experimental animal species.
Role of opioid receptors in NMDA receptor-mediated functions: hyperalgesia and allodynia
It has been well-demonstrated that activation of NMDA receptors contributes to hyperalgesia associated with nerve injury or inflammation. In a rat model of nerve injury induced by loose ligation of the common sciatic nerve (the CCI model), morphine given i.v. or i.t. reduced thermal hyperalgesia 6, 83, although the effect of morphine on reversal of thermal hyperalgesia deteriorated rapidly in CCI rats after two doses of morphine treatment [83]. In a rat model of hind paw inflammation [53], the κ
Intracellular events related to interactions between NMDA and opioid receptors
The intracellular events following NMDA receptor activation have been described in detail elsewhere [82]. The key step is the elevation of intracellular Ca2+ concentration followed by PKC activation 2, 101and the production of NO, a novel neural messenger [24]. The following sections discuss the contribution of intracellular events subsequent to NMDA receptor activation to mechanisms of some opioid receptor-mediated phenomena including tolerance. Cellular and intracellular models regarding
Clinical implications
Recent progress in investigating neural mechanisms subserving neuropathic and inflammatory pain as well as opioid tolerance has significantly advanced our knowledge about pain and pain modulation. These studies represent two important frontiers in pain research. First, studies on the involvement of excitatory amino acid receptors, particularly NMDA receptors, as well as the associated intracellular events in mechanisms of neuropathic and inflammatory pain have led to the concept that
Summary and perspectives
A considerable number of studies have provided a large body of information concerning interactions between NMDA and opioid receptors. These findings may be summarized as follows.
(1) There exists a general overlap between distribution patterns of NMDA and opioid receptors within the CNS. Evidence exists for the co-localization of all three subtypes of opioid receptors as well as the co-localization of μ-opioid receptors and NMDA receptors within a single neuron both in the brain and spinal cord
Acknowledgements
Portions of this work were supported by US PHS grant DA08835. The author likes to thank Drs. David J. Mayer and Donald D. Price for their comments on an early version of this manuscript.
References (139)
- et al.
Behavioral evidence that systemic morphine may modulate a phasic pain-related behavior in a rat model of peripheral mononeuropathy
Pain
(1991) - et al.
Immunocytochemical localization of delta opioid receptors in mouse brain
J. Chem. Neuroanat.
(1995) - et al.
The NMDA receptor antagonist, MK-801, prevents long-lasting non-associative morphine tolerance in the rat
Brain Res.
(1992) - et al.
Blockade of the polyamine site of NMDA receptors produces antinociception and enhances the effect of morphine, in mice
Eur. J. Pharmacol.
(1996) - et al.
Intra-accumbens administration of NMDA receptor antagonist (±)CPP prevents locomotor activation conditioned by morphine and amphetamine in rats
Pharmacol. Biochem. Behav.
(1996) Non-competitive antagonism of N-methyl-d-aspartate receptor inhibits tolerance to the analgesic action of U-50488H, a kappa-opiate receptor agonist in the rat
Gen. Pharmacol.
(1995)Enhancement of morphine actions in morphine-naive and morphine-tolerant mice by LY 235959, a competitive antagonist of the NMDA receptor
Gen. Pharmacol.
(1997)- et al.
Modification of the binding of []MK-801 to brain regions and spinal cord of rats treated chronically with U-50488H, a kappa-opioid receptor agonist
Brain Res.
(1997) - et al.
Effect of dizocilpine (MK-801) on analgesia and tolerance induced by U-50488H, a kappa-opioid receptor agonist, in the mouse
Brain Res.
(1994) - et al.
Differential effects of LY235959, a competitive antagonist of the NMDA receptor on kappa-opioid receptor agonist induced responses in mice and rats
Brain Res.
(1997)
Effects of N-methyl-d-aspartate receptor antagonists on the analgesia and tolerance to d-Ala2, Glu4 deltorphin II, a delta 2-opioid receptor agonist in mice
Brain Res.
Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective mu or delta opioid agonists in mice
Pain
Immunocytochemical distribution of ionotropic glutamate receptor subunits in the spinal cord of the rabbit
J. Chem. Neuroanat.
Nitric oxide, a novel neuronal messenger
Neuron
Sustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a μ-opioids
Neuron
Mu receptor binding of some commonly used opioids and their metabolites
Life Sci.
Distribution of kappa-opioid receptor mRNA in adult mouse brain: an in situ hybridization histochemistry study
Mol. Cell Neurosci.
Activity-dependent neuronal plasticity following tissue injury and inflammation
Trends Neurosci.
Dynorphin potentiation of []CGP-39653 binding to rat brain membranes
Eur. J. Pharmacol.
Ketobemidone, methadone and pethidine are non-competitive N-methyl-d-aspartate (NMDA) antagonists in the rat cortex and spinal cord
Neurosci. Lett.
Dextromethorphan attenuates and reverses analgesic tolerance to morphine
Pain
The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-l-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids
Pain
Distinct distributions of mu, delta and kappa opioid receptor mRNA in rat brain
Biochem. Biophys. Res. Commun.
Ultrastructural localization and comparative distribution of nitric oxide synthase and N-methyl-d-aspartate receptors in the shell of the rat nucleus accumbens
Brain Res.
Immunohistochemical localization of mu-opioid receptors in rat brain using antibodies generated against a peptide sequence present in a purified mu-opioid binding protein
Neuroscience
Effect of transient naloxone antagonism on tolerance development in rats receiving continuous spinal morphine infusion
Pain
High-dose alfentanil pre-empts pain after abdominal hysterectomy
Pain
Blockade of morphine-induced hind limb myoclonic seizures in mice by ketamine
Pharmacol. Biochem. Behav.
1-Aminocyclopropane carboxylic acid (ACPC) prevents mu and delta opioid tolerance
Life Sci.
Targeted construction of phosphorylation-independent beta-arrestin mutants with constitutive activity in cells
J. Biol. Chem.
Mu and delta opioid receptors are differentially desensitized by the co-expression of beta-adrenergic receptor kinase 2 and beta-arrestin 2 in Xenopus oocytes
J. Biol. Chem.
Increased N-methyl-d-aspartate (NMDA) activity in the mouse spinal cord following morphine does not mediate opioid withdrawal
Brain Res.
NMDA R1 mRNA distribution in motor and thalamic-projecting sensory neurons in the rat spinal cord and brain stem
Neurosci. Lett.
Blockade of morphine-induced analgesia and tolerance in mice by MK-801
Brain Res.
Inhibition of morphine tolerance by NMDA receptor antagonists in the formalin test
Brain Res.
Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance
Pain
Immunohistochemical localization of the cloned mu-opioid receptor in the rat CNS
J. Chem. Neuroanat.
Kappa 1 receptor mRNA distribution in the rat CNS: comparison to kappa receptor binding and prodynorphin mRNA
Mol. Cell Neurosci.
Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats
Pain
Antinociceptive tolerance to the mu-opioid agonist DAMGO is dose-dependently reduced by MK-801 in rats
Neurosci. Lett.
Mechanisms of hyperalgesia and opiate tolerance: a current view of their possible interactions
Pain
Experimental mononeuropathy reduces the antinociceptive effects of morphine: implications for common intracellular mechanisms involved in morphine tolerance and neuropathic pain
Pain
Intrathecal MK-801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy
Brain Res.
Increases in protein kinase C gamma immunoreactivity in the spinal cord of rats associated with tolerance to the analgesic effects of morphine
Brain Res.
Delayed application of MK-801 attenuates development of morphine tolerance in rats
Brain Res.
Mechanisms of opioid tolerance
Pain Forum
The development of morphine tolerance and dependence is associated with translocation of protein kinase C
Pain
Affinity profiles of morphine, codeine, dihydrocodeine and their glucuronides at opioid receptor subtypes
Life Sci.
A protein kinase inhibitor, H7, inhibits the development of tolerance to opioid antinociception
Eur. J. Pharmacol.
Influence of chronic morphine treatment on protein kinase C activity: comparison with butorphanol and implication for opioid tolerance
Brain Res.
Cited by (250)
Clinical benefits and risks of N-methyl-D-aspartate receptor antagonists to treat severe opioid use disorder: A systematic review
2020, Drug and Alcohol DependenceSumatriptan effects on morphine-induced antinociceptive tolerance and physical dependence: The role of nitric oxide
2018, European Journal of PharmacologyInvolvement of NMDA receptors in the antidepressant-like effect of tramadol in the mouse forced swimming test
2017, Brain Research BulletinKynurenic acid and its analogue can alter the opioid receptor G-protein signaling after acute treatment via NMDA receptor in rat cortex and striatum
2017, Journal of the Neurological Sciences