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

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 const... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America June 14, 2016, Vol.113(24), pp.E3441-E3450
Main Author: Grace, Peter M
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1602070113
Link: http://search.proquest.com/docview/1797542305/?pq-origsite=primo
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title: Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation.
format: Article
creator:
  • 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
subjects:
  • Animals–Metabolism
  • Chronic Pain–Pathology
  • Clozapine–Physiopathology
  • Inflammasomes–Analogs & Derivatives
  • Interleukin-1beta–Pharmacology
  • Male–Metabolism
  • Microglia–Metabolism
  • Morphine–Metabolism
  • Nlr Family, Pyrin Domain-Containing 3 Protein–Pathology
  • Neuralgia–Pharmacology
  • Rats–Metabolism
  • Rats, Inbred F344–Metabolism
  • Rats, Sprague-Dawley–Pathology
  • Spinal Cord Dorsal Horn–Physiopathology
  • Spinal Cord Dorsal Horn–Metabolism
  • Spinal Cord Dorsal Horn–Pathology
  • Spinal Cord Dorsal Horn–Physiopathology
  • Il1b Protein, Rat
  • Inflammasomes
  • Interleukin-1beta
  • Nlr Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 Protein, Rat
  • Morphine
  • Clozapine
  • Clozapine N-Oxide
  • Damp
  • P2x7r
  • Tlr4
  • Danger Signals
  • Opioid-Induced Hyperalgesia
ispartof: Proceedings of the National Academy of Sciences of the United States of America, June 14, 2016, Vol.113(24), pp.E3441-E3450
description: 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-1[beta] (IL-1[beta]). 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. TLR4 | P2X7R | danger signals | DAMP | opioid-induced hyperalgesia
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1602070113
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleMorphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation.
creatorGrace, 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
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ispartofProceedings of the National Academy of Sciences of the United States of America, June 14, 2016, Vol.113(24), pp.E3441-E3450
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1602070113
subjectAnimals–Metabolism ; Chronic Pain–Pathology ; Clozapine–Physiopathology ; Inflammasomes–Analogs & Derivatives ; Interleukin-1beta–Pharmacology ; Male–Metabolism ; Microglia–Metabolism ; Morphine–Metabolism ; Nlr Family, Pyrin Domain-Containing 3 Protein–Pathology ; Neuralgia–Pharmacology ; Rats–Metabolism ; Rats, Inbred F344–Metabolism ; Rats, Sprague-Dawley–Pathology ; Spinal Cord Dorsal Horn–Physiopathology ; Spinal Cord Dorsal Horn–Metabolism ; Spinal Cord Dorsal Horn–Pathology ; Spinal Cord Dorsal Horn–Physiopathology ; Il1b Protein, Rat ; Inflammasomes ; Interleukin-1beta ; Nlr Family, Pyrin Domain-Containing 3 Protein ; Nlrp3 Protein, Rat ; Morphine ; Clozapine ; Clozapine N-Oxide ; Damp ; P2x7r ; Tlr4 ; Danger Signals ; Opioid-Induced Hyperalgesia
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descriptionOpioid 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-1[beta] (IL-1[beta]). 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. TLR4 | P2X7R | danger signals | DAMP | opioid-induced hyperalgesia
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titleMorphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation.
authorGrace, 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...
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