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

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.

Cited by papers we hold 3

• Roles of β-Endorphin in Stress, Behavior, Neuroinflammation, and Brain Energy Metabolism · 2020
  No notice
• The effect of gut microbiome on tolerance to morphine mediated antinociception in mice · 2017
  No notice
• Stress-Induced Visceral Pain: Toward Animal Models of Irritable-Bowel Syndrome and Associated Comorbidities · 2015
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.