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.

Glia in pathological pain: A role for fractalkine

“…A recent report showed spinal TLR4 antagonism during sciatic nerve damage that leads to neuropathic pain in rats potently alleviated pathological pain (Hutchinson et al, 2007). In addition, this study was the first to demonstrate that, like neuropathic pain, opioids activate glia via TLR4 activation that leads to opioid-induced tolerance (Hutchinson et al, 2007). These findings have profound implications on future treatment strategies for clinically utilized opioids, as TLR activation appears to play a significant role in neuropathic pain.…”

“…Further, blocking spinal cord TLR4 production in neuropathic rats also blocked pathological pain and microglial/macrophage activation (Tanga et al, 2005), supporting that TLR4 signaling in the spinal cord is important for mediating neuropathic pain. A recent report showed spinal TLR4 antagonism during sciatic nerve damage that leads to neuropathic pain in rats potently alleviated pathological pain (Hutchinson et al, 2007). In addition, this study was the first to demonstrate that, like neuropathic pain, opioids activate glia via TLR4 activation that leads to opioid-induced tolerance (Hutchinson et al, 2007).…”

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

“…Previous studies have shown that opioid receptors are [3,32,33] . After chronic or acute exposure to morphine, activated neurons and glia exhibit increased expression of pro-infl ammatory cytokines, such as TNF-α, IL-1β, IL-6 [19,34,35] , and chemokines [36,37] .…”

Medication-overuse headache and opioid-induced hyperalgesia: A review of mechanisms, a neuroimmune hypothesis and a novel approach to treatment

“…118 This dual activity at both neuronal and glial cells is common with other clinically relevant opioids. 115 It has recently been demonstrated that morphine-3-glucuronide has TLR-4 agonist activity, indicating that codeine and morphine metabolites may contribute to this action. 119 For a detailed discussion regarding the role of TLR-4 in opioid-induced glial activation see review by Watkins at al.…”

“…107 Pre-clinically opioid-induced glial activation is known to oppose opioid analgesia and enhance opioid adverse effects including tolerance, dependence, reward and respiratory depression. 115,116 Interestingly, opioid-induced glial activation is mediated through activation of TLR-4, exposing the potential to separate the beneficial actions of opioids from their unwanted adverse effects. 92 Pre-clinical studies have demonstrated that while morphine administration results in analgesia via agonism at the μ-opioid receptor on the neurons, it is also activates glial cells via TLR-4, resulting in the production of neuroexcitatory mediators.…”