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Volume 7 (2007), Pages 98-111
Mini-Review Article

Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward

1Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA
2Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, South Australia, 5005, Australia
3Avigen Inc., Alameda, CA, USA
4Chemical Biology Research Branch, National Institute on Drug Abuse, Bethesda, MD, USA

Received 20 June 2007; Revised 3 August 2007; Accepted 5 August 2007

Academic Editors: D. Shurtleff and S. Ferre

Copyright © 2007 Mark R. Hutchinson et al.


This review will introduce the concept of toll-like receptor (TLR)–mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine) level of analysis. Moreover, a novel antagonism of TLR4 by (+)- and (˗)-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia) and unwanted (tolerance, dependence, and reward) actions of opioids, thereby improving the safety and efficacy of their use.