title: Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences.
abstract: Opioid-induced glial activation and its proinflammatory consequences have been associated with both reduced acute opioid analgesia and the enhanced development of tolerance, hyperalgesia and allodynia following chronic opioid administration. Intriguingly, recent evidence demonstrates that these effects can result independently from the activation of classical, stereoselective opioid receptors. Here, a structurally disparate range of opioids cause activation of signaling by the innate immune receptor toll like receptor 4 (TLR4), resulting in proinflammatory glial activation. In the present series of studies, we demonstrate that the (+)-isomers of methadone and morphine, which bind with negligible affinity to classical opioid receptors, induced upregulation of proinflammatory cytokine and chemokine production in rat isolated dorsal spinal cord. Chronic intrathecal (+)-methadone produced hyperalgesia and allodynia, which were associated with significantly increased spinal glial activation (TLR4 mRNA and protein) and the expression of multiple chemokines and cytokines. Statistical analysis suggests that a cluster of cytokines and chemokines may contribute to these nociceptive behavioral changes. Acute intrathecal (+)-methadone and (+)-morphine were also found to induce microglial, interleukin-1 and TLR4/myeloid differentiation factor-2 (MD-2) dependent enhancement of pain responsivity. In silico docking analysis demonstrated (+)-naloxone sensitive docking of (+)-methadone and (+)-morphine to human MD-2. Collectively, these data provide the first evidence of the pro-nociceptive consequences of small molecule xenobiotic activation of spinal TLR4 signaling independent of classical opioid receptor involvement.
authors.affiliation: Department of Psychology, University of Colorado at Boulder, Boulder, CO 80309-0345, USA. mark.hutchinson@adelaide.edu.au
authors.forename: M R
authors.initials: MR
authors.lastname: Hutchinson
authors.forename: S S
authors.initials: SS
authors.lastname: Lewis
authors.forename: B D
authors.initials: BD
authors.lastname: Coats
authors.forename: N
authors.initials: N
authors.lastname: Rezvani
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: J L
authors.initials: JL
authors.lastname: Wieseler
authors.forename: A A
authors.initials: AA
authors.lastname: Somogyi
authors.forename: H
authors.initials: H
authors.lastname: Yin
authors.forename: S F
authors.initials: SF
authors.lastname: Maier
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
authors.forename: L R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000633:toxicity*; D007278:Injections, Spinal; D007375:Interleukin-1 / Q000378:metabolism; D007536:Isomerism; D051218:Lymphocyte Antigen 96 / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008691:Methadone / Q000633:toxicity; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009020:Morphine / Q000633:toxicity; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D051197:Toll-Like Receptor 4 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D018836:Inflammation Mediators; D007375:Interleukin-1; D051218:Lymphocyte Antigen 96; D012333:RNA, Messenger; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D009020:Morphine; D008691:Methadone