title: Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury.
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 10mg/kg/day morphine beginning 24h 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.
authors: University of Colorado Boulder, Department of Psychology and Neuroscience, Center for Neuroscience, Boulder, CO, USA.
authors: Amanda
authors: A
authors: Ellis
authors: University of Colorado Boulder, Department of Psychology and Neuroscience, Center for Neuroscience, Boulder, CO, USA; School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors: Peter M
authors: PM
authors: Grace
authors: University of Colorado Boulder, Department of Psychology and Neuroscience, Center for Neuroscience, Boulder, CO, USA.
authors: Julie
authors: J
authors: Wieseler
authors: University of Colorado Boulder, Department of Psychology and Neuroscience, Center for Neuroscience, Boulder, CO, USA.
authors: Jacob
authors: J
authors: Favret
authors: University of Colorado Boulder, Department of Psychology and Neuroscience, Center for Neuroscience, Boulder, CO, USA.
authors: Kendra
authors: K
authors: Springer
authors: University of Colorado Boulder, Department of Psychology and Neuroscience, Center for Neuroscience, Boulder, CO, USA.
authors: Bryce
authors: B
authors: Skarda
authors: University of Colorado Boulder, Department of Psychology and Neuroscience, Center for Neuroscience, Boulder, CO, USA.
authors: Monica
authors: M
authors: Ayala
authors: School of Medicine, University of Adelaide, Adelaide, SA, Australia; Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, Australia.
authors: Mark R
authors: MR
authors: Hutchinson
authors: Craig Hospital, Englewood, CO, USA.
authors: Scott
authors: S
authors: Falci
authors: Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA.
authors: Kenner C
authors: KC
authors: Rice
authors: University of Colorado Boulder, Department of Psychology and Neuroscience, Center for Neuroscience, Boulder, CO, USA.
authors: Steven F
authors: SF
authors: Maier
authors: University of Colorado Boulder, Department of Psychology and Neuroscience, Center for Neuroscience, Boulder, CO, USA. Electronic address: linda.watkins@colorado.edu.
authors: Linda R
authors: LR
authors: Watkins
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D006930:Hyperalgesia / Q000150:complications / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009271:Naltrexone / Q000008:administration & dosage; D009437:Neuralgia / Q000150:complications / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000150:complications / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D009271:Naltrexone; D009020:Morphine
keywords: (+)-Naltrexone; Inflammasome; Interleukin-1β; NLRP3; Neuropathic pain; Proinflammatory cytokines; Rats; TLR4; Tumor necrosis factor