title: Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation.
abstract: Opioid 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.
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309; Discipline of Pharmacology, School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia; peter.grace@colorado.edu.
authors.forename: Peter M
authors.identifier: 0000-0002-8999-1220
authors.initials: PM
authors.lastname: Grace
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Keith A
authors.initials: KA
authors.lastname: Strand
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Erika L
authors.initials: EL
authors.lastname: Galer
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599;
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Urban
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309; Chemical Biology Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309; BioFrontiers Institute, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Michael V
authors.initials: MV
authors.lastname: Baratta
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Fabisiak
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Anderson
authors.affiliation: Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892;
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Lisa I
authors.initials: LI
authors.lastname: Greene
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Debra
authors.initials: D
authors.lastname: Berkelhammer
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Yingning
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Ellis
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309; BioFrontiers Institute, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309; Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100082, China.
authors.forename: Hang Hubert
authors.initials: HH
authors.lastname: Yin
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Serge
authors.initials: S
authors.lastname: Campeau
authors.affiliation: Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892;
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599;
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D000818:Animals; D059350:Chronic Pain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009020:Morphine / Q000494:pharmacology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: C000594089:IL1B protein, rat; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D009020:Morphine; D003024:Clozapine; C079149:clozapine N-oxide
keywords: DAMP; P2X7R; TLR4; danger signals; opioid-induced hyperalgesia