Sex differences in innate immunity and its impact on opioid pharmacology

Abstract

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 mu 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 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.

Differences in neuroimmune signalling between male and female patients suffering from knee osteoarthritis

“…We postulated that proinflammatory substances involved in direct bloodborne immune communication between periphery and CNS would be characterized by a) elevated concentrations in the CSF and, b) concentrations of the particular substance would correlate across the different compartments, i.e., CSF, serum and synovial fluid (SF). Given that chronic pain is more common in women and that sex differences in innate immune reactions have potential relevance for these differences (Levine et al 2006, Karschikoff et al 2015, Doyle and Murphy 2017, Rosen et al 2017, we chose to include sex differences in our analysis.…”

Analgesia and mouse strain influence neuromuscular plasticity in inflamed intestine

“…While we used male animals to minimize variation, we acknowledge that it is likely that analgesia will be less effective on females here as elsewhere, by extrapolation from evidence that morphine is a more potent analgesic in males than in females . Furthermore, it is important to note the interaction of μ‐opioid agonists such as morphine with elements of the innate immune system, which is itself dimorphic in significant ways, and may influence outcomes in inflammatory pain …”

“…40 Furthermore, it is important to note the interaction of μ-opioid agonists such as morphine with elements of the innate immune system, which is itself dimorphic in significant ways, and may influence outcomes in inflammatory pain. 41 We used tramadol according to standard practice, as it has been used widely in rodents and shown effective in mice and rats on diverse models of pain in recent years, whether arising as neuropathic pain, postsurgical pain, or formalin-induced pain. 17,[42][43][44][45][46][47] There is little similar work in rodent models of intestinal inflammation, where its use has been neglected.…”

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

“…Numerous instances at the behavioral and mechanistic level can now be cited to dispute this assertion. 14,15 Many models’ threshold measurements. Alternative models employ “spontaneous behaviors”, including general activity, rearing, weight bearing and gait as markers of an aversive condition.…”

“…Numerous instances at the behavioral and mechanistic level can now be cited to dispute this assertion. 14,15 …”