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.