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Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation

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dc.contributor.authorGrace, P.
dc.contributor.authorStrand, K.
dc.contributor.authorGaler, E.
dc.contributor.authorUrban, D.
dc.contributor.authorWang, X.
dc.contributor.authorBaratta, M.
dc.contributor.authorFabisiak, T.
dc.contributor.authorAnderson, N.
dc.contributor.authorCheng, K.
dc.contributor.authorGreene, L.
dc.contributor.authorBerkelhammer, D.
dc.contributor.authorZhang, Y.
dc.contributor.authorEllis, A.
dc.contributor.authorYin, H.
dc.contributor.authorCampeau, S.
dc.contributor.authorRicei, K.
dc.contributor.authorRoth, B.
dc.contributor.authorMaier, S.
dc.contributor.authorWatkins, L.
dc.date.issued2016
dc.description.abstractOpioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain—namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent “two-hit hypothesis” of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain.
dc.description.statementofresponsibilityPeter M. Grace, Keith A. Strand, Erika L. Galer, Daniel J. Urban, Xiaohui Wang, Michael V. Baratta, Timothy J. Fabisiak, Nathan D. Anderson, Kejun Cheng, Lisa I. Greene, Debra Berkelhammer, Yingning Zhang, Amanda L. Ellis, Hang Hubert Yin, Serge Campeau, Kenner C. Rice, Bryan L. Roth, Steven F. Maier and Linda R. Watkins
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2016; 113(24):E3441-E3450
dc.identifier.doi10.1073/pnas.1602070113
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.orcidGrace, P. [0000-0002-8999-1220]
dc.identifier.urihttp://hdl.handle.net/2440/102824
dc.language.isoen
dc.publisherNational Academy of Sciences
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1054091
dc.rightsCopyright status unknown
dc.source.urihttps://doi.org/10.1073/pnas.1602070113
dc.subjectMicroglia
dc.subjectAnimals
dc.subjectRats, Inbred F344
dc.subjectRats
dc.subjectRats, Sprague-Dawley
dc.subjectNeuralgia
dc.subjectMorphine
dc.subjectClozapine
dc.subjectMale
dc.subjectInterleukin-1beta
dc.subjectInflammasomes
dc.subjectChronic Pain
dc.subjectSpinal Cord Dorsal Horn
dc.subjectNLR Family, Pyrin Domain-Containing 3 Protein
dc.titleMorphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation
dc.typeJournal article
pubs.publication-statusPublished

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