title: Exploring the neuroimmunopharmacology of opioids: an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia.
abstract: Vastly stimulated by the discovery of opioid receptors in the early 1970s, preclinical and clinical research was directed at the study of stereoselective neuronal actions of opioids, especially those played in their crucial analgesic role. However, during the past decade, a new appreciation of the non-neuronal actions of opioids has emerged from preclinical research, with specific appreciation for the nonclassic and nonstereoselective sites of action. Opioid activity at Toll-like receptors, newly recognized innate immune pattern recognition receptors, adds substantially to this unfolding story. It is now apparent from molecular and rodent data that these newly identified signaling events significantly modify the pharmacodynamics of opioids by eliciting proinflammatory reactivity from glia, the immunocompetent cells of the central nervous system. These central immune signaling events, including the release of cytokines and chemokines and the associated disruption of glutamate homeostasis, cause elevated neuronal excitability, which subsequently decreases opioid analgesic efficacy and leads to heightened pain states. This review will examine the current preclinical literature of opioid-induced central immune signaling mediated by classic and nonclassic opioid receptors. A unification of the preclinical pharmacology, neuroscience, and immunology of opioids now provides new insights into common mechanisms of chronic pain, naive tolerance, analgesic tolerance, opioid-induced hyperalgesia, and allodynia. Novel pharmacological targets for future drug development are discussed in the hope that disease-modifying chronic pain treatments arising from the appreciation of opioid-induced central immune signaling may become practical.
authors.affiliation: Discipline of Pharmacology, School of Medical Science, University of Adelaide, South Australia, Australia, 5005. mark.hutchinson@adelaide.edu.au
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Shavit
authors.forename: Peter M
authors.initials: PM
authors.lastname: Grace
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D000698:Analgesia / Q000009:adverse effects; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000187:drug effects* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009292:Narcotic Antagonists; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009419:Nerve Tissue Proteins; D017472:Receptors, Interleukin-1; D011957:Receptors, Opioid; D051193:Toll-Like Receptors