title: Combined inhibition of FAAH and COX produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models.
abstract: Common pharmacological treatments of neuropathic and chronic inflammatory pain conditions generally lack efficacy and/or are associated with significant untoward side effects. However, recent preclinical data indicate that combined inhibition of cyclooxygenase (COX) and fatty acid amide hydrolase (FAAH), the primary catabolic enzyme of the endocannabinoid N-arachidonoylethanolamine (anandamide; AEA), produces enhanced antinociceptive effects in a variety of murine models of pain. Accordingly, the primary objective of the present study was to investigate the consequences of co-administration of the COX inhibitor diclofenac and the highly selective FAAH inhibitor PF-3845 in models of neuropathic pain (i.e., chronic constrictive injury of the sciatic nerve (CCI)) and inflammatory pain induced by an intraplantar injection of carrageenan. Here, we report that combined administration of subthreshold doses of these drugs produced enhanced antinociceptive effects in CCI and carrageenan pain models, the latter of which was demonstrated to require both CB1 and CB2 receptors. The combined administration of subthreshold doses of these drugs also increased AEA levels and decreased prostaglandin levels in whole brain. Together, these data add to the growing research that dual blockade of FAAH and COX represents a potential therapeutic strategy for the treatment of neuropathic and inflammatory pain states.
  
  
  CONCLUSIONS
  Tandem inhibition of FAAH and COX attenuates inflammatory and neuropathic pain states, which may avoid potentially harmful side effects of other therapeutic options, such as NSAIDs or opioids.
authors: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA. Electronic address: grimtw@vcu.edu.
authors: Travis W
authors: TW
authors: Grim
authors: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors: Sudeshna
authors: S
authors: Ghosh
authors: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
authors: Ku-Lung
authors: KL
authors: Hsu
authors: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
authors: Benjamin F
authors: BF
authors: Cravatt
authors: Department of Psychology, West Virginia University, Morgantown, WV 26506, USA.
authors: Steven G
authors: SG
authors: Kinsey
authors: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors: Aron H
authors: AH
authors: Lichtman
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000188:drug therapy*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D000099252:Fatty Acid Amide Hydrolases
keywords: Cannabinoid; Cyclooxygenase (COX); Endogenous cannabinoid (endocannabinoid); Fatty acid amide hydrolase; Fatty acid metabolism; Inflammation; Inflammatory pain; Neuropathic pain; Neuropathy; Pain; Prostaglandins