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Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation.
Grace, Peter M; Strand, Keith A; Galer, Erika L; Urban, Daniel J; Wang, Xiaohui; Baratta, Michael V; Fabisiak, Timothy J; Anderson, Nathan D; Cheng, Kejun; Greene, Lisa I; Berkelhammer, Debra; Zhang, Yingning; Ellis, Amanda L; Yin, Hang Hubert; Campeau, Serge; Rice, Kenner C; Roth, Bryan L; Maier, Steven F; Watkins, Linda R.
Affiliation
  • Grace PM; 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.
  • Strand KA; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
  • Galer EL; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
  • Urban DJ; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599;
  • Wang X; 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
  • Baratta MV; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
  • Fabisiak TJ; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
  • Anderson ND; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
  • Cheng K; Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892;
  • Greene LI; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
  • Berkelhammer D; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
  • Zhang Y; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
  • Ellis AL; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
  • Yin HH; 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 Univers
  • Campeau S; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
  • Rice KC; Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892;
  • Roth BL; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599;
  • Maier SF; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
  • Watkins LR; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Proc Natl Acad Sci U S A ; 113(24): E3441-50, 2016 06 14.
Article in En | MEDLINE | ID: mdl-27247388
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-1ß (IL-1ß). 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.
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Full text: 1 Database: MEDLINE Main subject: Microglia / Inflammasomes / Chronic Pain / Spinal Cord Dorsal Horn / NLR Family, Pyrin Domain-Containing 3 Protein / Morphine / Neuralgia Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2016 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Microglia / Inflammasomes / Chronic Pain / Spinal Cord Dorsal Horn / NLR Family, Pyrin Domain-Containing 3 Protein / Morphine / Neuralgia Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2016 Type: Article