Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury |
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| Affiliation: | 1. University of Colorado Boulder, Department of Psychology and Neuroscience, Center for Neuroscience, Boulder, CO, USA;2. School of Medicine, University of Adelaide, Adelaide, SA, Australia;3. Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, Australia;4. Craig Hospital, Englewood, CO, USA;5. Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA;1. Institute of Medical Microbiology, University of Duisburg-Essen, 45147 Essen, Germany;2. Department of Chemistry, University of Natural Resources and Life Sciences, 1190 Vienna, Austria;1. The Nordic Cochrane Centre, Rigshospitalet, Dept 7810, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark;2. Department of Clinical Pharmacy, University of California, San Francisco, Suite 420, Box 0613, 3333 California Street, San Francisco, CA 94118 USA;3. Institute for Health Policy Studies, University of California, San Francisco, Suite 420, Box 0613, 3333 California Street, San Francisco, CA 94118 USA;1. Center for Biomedical Research on Pain (CBRP), College of Medicine, Xi׳an Jiaotong University, Xi׳an 710061, PR China;2. Institute of Biomedicine/Physiology, University of Helsinki, POB 63, Helsinki 00014, Finland |
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| Abstract: | Central neuropathic pain (CNP) is a pervasive, debilitating problem that impacts thousands of people living with central nervous system disorders, including spinal cord injury (SCI). Current therapies for treating this type of pain are ineffective and often have dose-limiting side effects. Although opioids are one of the most commonly used CNP treatments, recent animal literature has indicated that administering opioids shortly after a traumatic injury can actually have deleterious effects on long-term health and recovery. In order to study the deleterious effects of administering morphine shortly after trauma, we employed our low thoracic (T13) dorsal root avulsion model (Spinal Neuropathic Avulsion Pain, SNAP). Administering a weeklong course of 10 mg/kg/day morphine beginning 24 h after SNAP resulted in amplified mechanical allodynia. Co-administering the non-opioid toll-like receptor 4 (TLR4) antagonist (+)-naltrexone throughout the morphine regimen prevented morphine-induced amplification of SNAP. Exploration of changes induced by early post-trauma morphine revealed that this elevated gene expression of TLR4, TNF, IL-1β, and NLRP3, as well as IL-1β protein at the site of spinal cord injury. These data suggest that a short course of morphine administered early after spinal trauma can exacerbate CNP in the long term. TLR4 initiates this phenomenon and, as such, may be potential therapeutic targets for preventing the deleterious effects of administering opioids after traumatic injury. |
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| Keywords: | TLR4 Inflammasome Proinflammatory cytokines (+)-Naltrexone Interleukin-1β NLRP3 Tumor necrosis factor Neuropathic pain Rats |
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