Sex differences in innate immunity and its impact on opioid pharmacology.

Morphine has been and continues to be one of the most potent and widely used drugs for the treatment of pain. Clinical and animal models investigating sex differences in pain and analgesia demonstrate that morphine is a more potent analgesic in males than in females. In addition to binding to the neuronal μ-opioid receptor, morphine binds to the innate immune receptor toll-like receptor 4 (TLR4), located on glial cells. Activation of glial TLR4 initiates a neuroinflammatory response that directly opposes morphine analgesia. Females of many species have a more active immune system than males; however, few studies have investigated glial cells as a potential mechanism driving sexually dimorphic responses to morphine. This Mini-Review illustrates the involvement of glial cells in key processes underlying observed sex differences in morphine analgesia and suggests that targeting glia may improve current treatment strategies for pain.