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

• Verfasst von: Bishay, Philipp [VerfasserIn]
• Verfasst von: Schmidt, Helmut [VerfasserIn]
• Verfasst von: Marian, Claudiu [VerfasserIn]
• Verfasst von: Häussler, Annett [VerfasserIn]
• Verfasst von: Wijnvoord, Nina [VerfasserIn]
• Verfasst von: Ziebell, Simone [VerfasserIn]
• Verfasst von: Metzner, Julia [VerfasserIn]
• Verfasst von: Koch, Marco [VerfasserIn]
• Verfasst von: Myrczek, Thekla [VerfasserIn]
• Verfasst von: Bechmann, Ingo Jürgen [VerfasserIn]
• Verfasst von: Kuner, Rohini [VerfasserIn]
• Verfasst von: Costigan, Michael [VerfasserIn]
• Verfasst von: Dehghani, Faramarz [VerfasserIn]
• Verfasst von: Geisslinger, Gerd [VerfasserIn]
• Verfasst von: Tegeder, Irmgard [VerfasserIn]
• Titel: R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids
• Verf.angabe: 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
• E-Jahr: 2010
• Jahr: May 13, 2010
• Umfang: 15 S.
• Fussnoten: Gesehen am 07.02.2023
• Titel Quelle: Enthalten in: PLOS ONE
• Ort Quelle: San Francisco, California, US : PLOS, 2006
• Jahr Quelle: 2010
• Band/Heft Quelle: 5(2010), 5, Artikel-ID e10628, Seite 1-15
• ISSN Quelle: 1932-6203
• DOI: doi:10.1371/journal.pone.0010628
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Endocannabinoids
• Sach-SW: Glutamate
• Sach-SW: Microglial cells
• Sach-SW: Neuropathic pain
• Sach-SW: Sciatic nerves
• Sach-SW: Spinal cord
• Sach-SW: Spinal cord injury
• Sach-SW: Spinal nerves
• K10plus-PPN: 1833429672

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.