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

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          Significance

          Pain after disease/damage of the nervous system is predominantly treated with opioids, but without exploration of the long-term consequences. We demonstrate that a short course of morphine after nerve injury doubles the duration of neuropathic pain. Using genetic and pharmacological interventions, and innovative Designer Receptor Exclusively Activated by Designer Drugs disruption of microglia reactivity, we demonstrate that opioid-prolonged neuropathic pain arises from spinal microglia and NOD-like receptor protein 3 inflammasome formation/activation. Inhibiting these processes permanently resets amplified pain to basal levels, an effect not previously reported. These data support the “two-hit hypothesis” of amplification of microglial activation—nerve injury being the first “hit,” morphine the second. The implications of such potent microglial “priming” has fundamental clinical implications for pain and may extend to many chronic neurological disorders.

          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.

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          Most cited references60

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          A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man

          A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve. The postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain (or dysesthesia) were produced. Hyperalgesic responses to noxious radiant heat were evident on the second postoperative day and lasted for over 2 months. Hyperalgesic responses to chemogenic pain were also present. The presence of allodynia was inferred from the nocifensive responses evoked by standing on an innocuous, chilled metal floor or by innocuous mechanical stimulation, and by the rats' persistence in holding the hind paw in a guarded position. The presence of spontaneous pain was suggested by a suppression of appetite and by the frequent occurrence of apparently spontaneous nocifensive responses. The affected hind paw was abnormally warm or cool in about one-third of the rats. About one-half of the rats developed grossly overgrown claws on the affected side. Experiments with this animal model may advance our understanding of the neural mechanisms of neuropathic pain disorders in humans.
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            Pathological pain and the neuroimmune interface.

            Reciprocal signalling between immunocompetent cells in the central nervous system (CNS) has emerged as a key phenomenon underpinning pathological and chronic pain mechanisms. Neuronal excitability can be powerfully enhanced both by classical neurotransmitters derived from neurons, and by immune mediators released from CNS-resident microglia and astrocytes, and from infiltrating cells such as T cells. In this Review, we discuss the current understanding of the contribution of central immune mechanisms to pathological pain, and how the heterogeneous immune functions of different cells in the CNS could be harnessed to develop new therapeutics for pain control. Given the prevalence of chronic pain and the incomplete efficacy of current drugs--which focus on suppressing aberrant neuronal activity--new strategies to manipulate neuroimmune pain transmission hold considerable promise.
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              A clinical perspective of IL-1β as the gatekeeper of inflammation.

              An expanding spectrum of acute and chronic non-infectious inflammatory diseases is uniquely responsive to IL-1β neutralization. IL-1β-mediated diseases are often called "auto-inflammatory" and the dominant finding is the release of the active form of IL-1β driven by endogenous molecules acting on the monocyte/macrophage. IL-1β activity is tightly controlled and requires the conversion of the primary transcript, the inactive IL-1β precursor, to the active cytokine by limited proteolysis. Limited proteolysis can take place extracellularly by serine proteases, released in particular by infiltrating neutrophils or intracellularly by the cysteine protease caspase-1. Therefore, blocking IL-1β resolves inflammation regardless of how the cytokine is released from the cell or how the precursor is cleaved. Endogenous stimulants such as oxidized fatty acids and lipoproteins, high glucose concentrations, uric acid crystals, activated complement, contents of necrotic cells, and cytokines, particularly IL-1 itself, induce the synthesis of the inactive IL-1β precursor, which awaits processing to the active form. Although bursts of IL-1β precipitate acute attacks of systemic or local inflammation, IL-1β also contributes to several chronic diseases. For example, ischemic injury, such as myocardial infarction or stroke, causes acute and extensive damage, and slowly progressive inflammatory processes take place in atherosclerosis, type 2 diabetes, osteoarthritis and smoldering myeloma. Evidence for the involvement of IL-1β and the clinical results of reducing IL-1β activity in this broad spectrum of inflammatory diseases are the focus of this review. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                14 June 2016
                31 May 2016
                : 113
                : 24
                : E3441-E3450
                Affiliations
                [1] aDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309;
                [2] bThe Center for Neuroscience, University of Colorado, Boulder, CO 80309;
                [3] cDiscipline of Pharmacology, School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia;
                [4] dDepartment of Pharmacology, University of North Carolina, Chapel Hill, NC 27599;
                [5] eChemical Biology Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China;
                [6] fDepartment of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309;
                [7] gBioFrontiers Institute, University of Colorado, Boulder, CO 80309;
                [8] hThe Center for Neuroscience, University of Colorado, Boulder, CO 80309;
                [9] iChemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892;
                [10] jCenter of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100082, China
                Author notes
                1To whom correspondence should be addressed. Email: peter.grace@ 123456colorado.edu .

                Edited by David Julius, University of California, San Francisco, CA, and approved April 19, 2016 (received for review February 16, 2016)

                Author contributions: P.M.G., X.W., M.V.B., H.H.Y., S.F.M., and L.R.W. designed research; P.M.G., K.A.S., E.L.G., X.W., M.V.B., T.J.F., N.D.A., L.I.G., D.B., Y.Z., A.L.E., and S.C. performed research; D.J.U., K.C., S.C., K.C.R., and B.L.R. contributed new reagents/analytic tools; P.M.G. analyzed data; and P.M.G., X.W., S.C., S.F.M., and L.R.W. wrote the paper.

                Author information
                http://orcid.org/0000-0002-8999-1220
                Article
                PMC4914184 PMC4914184 4914184 201602070
                10.1073/pnas.1602070113
                4914184
                27247388
                6d491ae2-d0cb-444f-9d84-25f398233535
                History
                Page count
                Pages: 10
                Funding
                Funded by: Department of Health, Australian Government | National Health and Medical Research Council (NHMRC) 501100000925
                Award ID: 1054091
                Funded by: National Natural Science Foundation of China (NSFC) 501100001809
                Award ID: 21543013
                Funded by: HHS | National Institutes of Health (NIH) 100000002
                Award ID: DE021966
                Funded by: HHS | National Institutes of Health (NIH) 100000002
                Award ID: DA023132
                Funded by: HHS | National Institutes of Health (NIH) 100000002
                Award ID: DA017204
                Funded by: HHS | National Institutes of Health (NIH) 100000002
                Award ID: U01MH105892
                Funded by: HHS | National Institutes of Health (NIH) 100000002
                Award ID: GM101279
                Categories
                PNAS Plus
                Biological Sciences
                Neuroscience
                PNAS Plus

                DAMP,opioid-induced hyperalgesia,TLR4,P2X7R,danger signals
                DAMP, opioid-induced hyperalgesia, TLR4, P2X7R, danger signals

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