R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids

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R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids

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dc.contributor.author Bishay, Philipp
dc.contributor.author Schmidt, Helmut
dc.contributor.author Marian, Claudiu
dc.contributor.author Häussler, Annett
dc.contributor.author Wijnvoord, Nina
dc.contributor.author Ziebell, Simone
dc.contributor.author Metzner, Julia
dc.contributor.author Koch, Marco
dc.contributor.author Myrczek, Thekla
dc.contributor.author Bechmann, Ingo
dc.contributor.author Kuner, Rohini
dc.contributor.author Dehghani, Faramarz
dc.contributor.author Geisslinger, Gerd
dc.contributor.author Tegeder, Irmgard
dc.contributor.author Costigan, Michael
dc.date.accessioned 2011-11-16T17:42:40Z
dc.date.issued 2010
dc.identifier.citation Bishay, Philipp, Helmut Schmidt, Claudiu Marian, Annett Häussler, Nina Wijnvoord, Simone Ziebell, Julia Metzner, and et al. 2010. R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids. PLoS ONE 5(5): e10628. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:5346718
dc.description.abstract Background: R-flurbiprofen, one of the enantiomers of flurbiprofen racemate, is inactive with respect to cyclooxygenase inhibition, but shows analgesic properties without relevant toxicity. Its mode of action is still unclear. Methodology/Principal Findings: We show that R-flurbiprofen reduces glutamate release in the dorsal horn of the spinal cord evoked by sciatic nerve injury and thereby alleviates pain in sciatic nerve injury models of neuropathic pain in rats and mice. This is mediated by restoring the balance of endocannabinoids (eCB), which is disturbed following peripheral nerve injury in the DRGs, spinal cord and forebrain. The imbalance results from transcriptional adaptations of fatty acid amide hydrolase (FAAH) and NAPE-phospholipase D, i.e. the major enzymes involved in anandamide metabolism and synthesis, respectively. R-flurbiprofen inhibits FAAH activity and normalizes NAPE-PLD expression. As a consequence, R-Flurbiprofen improves endogenous cannabinoid mediated effects, indicated by the reduction of glutamate release, increased activity of the anti-inflammatory transcription factor PPARγ and attenuation of microglia activation. Antinociceptive effects are lost by combined inhibition of CB1 and CB2 receptors and partially abolished in CB1 receptor deficient mice. R-flurbiprofen does however not cause changes of core body temperature which is a typical indicator of central effects of cannabinoid-1 receptor agonists. Conclusion: Our results suggest that R-flurbiprofen improves the endogenous mechanisms to regain stability after axonal injury and to fend off chronic neuropathic pain by modulating the endocannabinoid system and thus constitutes an attractive, novel therapeutic agent in the treatment of chronic, intractable pain. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi://10.1371/journal.pone.0010628 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869361/pdf/ en_US
dash.license LAA
dc.subject pharmacology en_US
dc.subject cell biology en_US
dc.subject cell signaling en_US
dc.subject neuroscience en_US
dc.subject behavioral neuroscience en_US
dc.subject neuronal and glial cell biology en_US
dc.subject anesthesiology and pain management en_US
dc.subject basic science of pain management en_US
dc.title R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author Costigan, Michael
dc.date.available 2011-11-16T17:42:40Z
dash.affiliation.other HMS^Neurology-Children's Hospital en_US

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