Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward. Journal Article uri icon

Overview

abstract

  • 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.

publication date

  • November 2, 2007

has restriction

  • gold

Date in CU Experts

  • October 4, 2013 2:39 AM

Full Author List

  • Hutchinson MR; Bland ST; Johnson KW; Rice KC; Maier SF; Watkins LR

author count

  • 6

Other Profiles

Electronic International Standard Serial Number (EISSN)

  • 1537-744X

Additional Document Info

start page

  • 98

end page

  • 111

volume

  • 7