title: R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: pharmazentrum frankfurt/ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Bishay
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidt
authors.forename: Claudiu
authors.initials: C
authors.lastname: Marian
authors.forename: Annett
authors.initials: A
authors.lastname: Häussler
authors.forename: Nina
authors.initials: N
authors.lastname: Wijnvoord
authors.forename: Simone
authors.initials: S
authors.lastname: Ziebell
authors.forename: Julia
authors.initials: J
authors.lastname: Metzner
authors.forename: Marco
authors.initials: M
authors.lastname: Koch
authors.forename: Thekla
authors.initials: T
authors.lastname: Myrczek
authors.forename: Ingo
authors.initials: I
authors.lastname: Bechmann
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
authors.forename: Michael
authors.initials: M
authors.lastname: Costigan
authors.forename: Faramarz
authors.initials: F
authors.lastname: Dehghani
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002186:Cannabinoids / Q000096:biosynthesis / Q000378:metabolism*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005480:Flurbiprofen / Q000494:pharmacology / Q000627:therapeutic use*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005971:Glutamates / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D009619:Nociceptors / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000473:pathology; D010739:Phospholipase D / Q000378:metabolism; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000172:deficiency; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D013997:Time Factors; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D015415:Biomarkers; D002186:Cannabinoids; D005480:Flurbiprofen; D005971:Glutamates; D010739:Phospholipase D; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases