Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation.
Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. In silico docking simulations indicate codeine also docks to MD2, an accessory protein for TLR4, suggesting potential to induce TLR4-dependent pain facilitation. We hypothesized codeine would cause TLR4-dependent hyperalgesia/allodynia that is disparate from its opioid receptor-dependent analgesic rank potency. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests at days 0, 3 and 5 in mice receiving intraperitoneal equimolar codeine (21 mg kg(-1)), morphine (20 mg kg(-1)) or saline, twice daily. This experiment was repeated in animals with prior partial nerve injury and in TLR4 null mutant mice. Interventions with interleukin-1 receptor antagonist (IL-1RA) and glial-attenuating drug ibudilast were assessed. Analyses of glial activation markers (glial fibrillary acid protein and CD11b) in neuronal tissue were conducted at the completion of behavioural testing. Despite providing less acute analgesia (P=0.006), codeine induced similar hotplate hyperalgesia to equimolar morphine vs saline (-9.5 s, P<0.01 and -7.3 s, P<0.01, respectively), suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity. This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity-although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.
Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
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Johnson
1] Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia [2] Pain and Anaesthesia Research Clinic, University of Adelaide, Adelaide, SA, Australia [3] Pain Management Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
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PE
Rolan
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
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ME
Johnson
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
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Bobrovskaya
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
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DB
Williams
Medicinova, San Diego, CA, USA.
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Johnson
School of Mathematical Sciences, University of Adelaide, Adelaide, SA, Australia.
J
J
Tuke
Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
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MR
Hutchinson
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003061:Codeine / Q000008:administration & dosage / Q000494:pharmacology*; D006930:Hyperalgesia / Q000139:chemically induced*; D053590:Interleukin 1 Receptor Antagonist Protein; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects*; D011897:Random Allocation; D012584:Sciatic Nerve / Q000293:injuries; D051197:Toll-Like Receptor 4
D000701:Analgesics, Opioid; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009020:Morphine; D003061:Codeine