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Watkins LR et al. – Glial activation participates in the mediation of pain including neuropathic pain, due to release of neuroexcitatory, proinflammatory products. Glial activation is now known to occur in response to opioids as well. Opioid–induced glial activation opposes opioid analgesia and enhances opioid tolerance, dependence, reward and respiratory depression. Such effects can occur, not via classical opioid receptors, but rather via non–stereoselective activation of toll–like receptor 4, a recently recognized key glial receptor participating in neuropathic pain as well.

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