Elsevier

Brain Research Reviews

Volume 30, Issue 3, November 1999, Pages 289-304
Brain Research Reviews

Full-length review
NMDA and opioid receptors: their interactions in antinociception, tolerance and neuroplasticity

https://doi.org/10.1016/S0165-0173(99)00020-XGet rights and content

Abstract

Over the last several years, significant progress has been made in our understanding of interactions between the N-methyl-d-aspartate (NMDA) and opioid receptors. Such interactions have been demonstrated at two distinct sites: (1) modulation of NMDA receptor-mediated electrophysiological events by opioids; and (2) intracellular events involving interactions between NMDA and opioid receptors. Furthermore, a considerable number of studies have shown the involvement of such interactions in neural mechanisms of nociceptive transmission, antinociception in acute and chronic pain states, opioid tolerance/dependence, and neuroplasticity. Importantly, emerging evidence indicates that activation of NMDA receptors may differentially modulate functions mediated by distinct opioid receptor subtypes, namely μ, δ, and κ receptors. These studies have greatly enriched our knowledge regarding both NMDA and opioid receptor systems and have shed light on neurobiology of both acute and chronic pain. The advancement of such knowledge also promotes new strategies for better clinical management of pain patients.

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.

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