R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.

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 gluta...

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Main Authors: Philipp Bishay, Helmut Schmidt, Claudiu Marian, Annett Häussler, Nina Wijnvoord, Simone Ziebell, Julia Metzner, Marco Koch, Thekla Myrczek, Ingo Bechmann, Rohini Kuner, Michael Costigan, Faramarz Dehghani, Gerd Geisslinger, Irmgard Tegeder
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2010-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC2869361?pdf=render
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spelling doaj-596553c07d6543f5abddf4d2a7a6f4a72020-11-25T01:30:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-01-0155e1062810.1371/journal.pone.0010628R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.Philipp BishayHelmut SchmidtClaudiu MarianAnnett HäusslerNina WijnvoordSimone ZiebellJulia MetznerMarco KochThekla MyrczekIngo BechmannRohini KunerMichael CostiganFaramarz DehghaniGerd GeisslingerIrmgard TegederBACKGROUND: 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 PPARgamma 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.http://europepmc.org/articles/PMC2869361?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Philipp Bishay
Helmut Schmidt
Claudiu Marian
Annett Häussler
Nina Wijnvoord
Simone Ziebell
Julia Metzner
Marco Koch
Thekla Myrczek
Ingo Bechmann
Rohini Kuner
Michael Costigan
Faramarz Dehghani
Gerd Geisslinger
Irmgard Tegeder
spellingShingle Philipp Bishay
Helmut Schmidt
Claudiu Marian
Annett Häussler
Nina Wijnvoord
Simone Ziebell
Julia Metzner
Marco Koch
Thekla Myrczek
Ingo Bechmann
Rohini Kuner
Michael Costigan
Faramarz Dehghani
Gerd Geisslinger
Irmgard Tegeder
R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.
PLoS ONE
author_facet Philipp Bishay
Helmut Schmidt
Claudiu Marian
Annett Häussler
Nina Wijnvoord
Simone Ziebell
Julia Metzner
Marco Koch
Thekla Myrczek
Ingo Bechmann
Rohini Kuner
Michael Costigan
Faramarz Dehghani
Gerd Geisslinger
Irmgard Tegeder
author_sort Philipp Bishay
title R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.
title_short R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.
title_full R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.
title_fullStr R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.
title_full_unstemmed R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.
title_sort r-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2010-01-01
description 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 PPARgamma 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.
url http://europepmc.org/articles/PMC2869361?pdf=render
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