Fatty acid amide hydrolase (FAAH) inhibitors exert pharmacological effects, but lack antinociceptive efficacy in rats with neuropathic spinal cord injury pain.
Amelioration of neuropathic spinal cord injury (SCI) pain is a clinical challenge. Increasing the endocannabinoid anandamide and other fatty acid amides (FAA) by blocking fatty acid amide hydrolase (FAAH) has been shown to be antinociceptive in a number of animal models of chronic pain. However, an antinociceptive effect of blocking FAAH has yet to be demonstrated in a rat model of neuropathic SCI pain. Four weeks following a SCI, rats developed significantly decreased hind paw withdrawal thresholds, indicative of below-level cutaneous hypersensitivity. A group of SCI rats were systemically treated (i.p.) with either the selective FAAH inhibitor URB597 or vehicle twice daily for seven days. A separate group of SCI rats received a single dose (p.o.) of either the selective FAAH inhibitor PF-3845 or vehicle. Following behavioral testing, levels of the FAA N-arachidonoylethanolamide, N-oleoyl ethanolamide and N-palmitoyl ethanolamide were quantified in brain and spinal cord from SCI rats. Four weeks following SCI, FAA levels were markedly reduced in spinal cord tissue. Although systemic treatment with URB597 significantly increased CNS FAA levels, no antinociceptive effect was observed. A significant elevation of CNS FAA levels was also observed following oral PF-3845 treatment, but only a modest antinociceptive effect was observed. Increasing CNS FAA levels alone does not lead to robust amelioration of below-level neuropathic SCI pain. Perhaps utilizing FAAH inhibition in conjunction with other analgesic mechanisms could be an effective analgesic therapy.
Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
Aldric T
AT
Hama
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
Peter
P
Germano
Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
Matthew S
MS
Varghese
Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America.
Benjamin F
BF
Cravatt
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
G Todd
GT
Milne
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
James P
JP
Pearson
Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
Jacqueline
J
Sagen
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D063388:Endocannabinoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006614:Hindlimb / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009437:Neuralgia / Q000209:etiology / Q000517:prevention & control*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000150:complications*; D016896:Treatment Outcome; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D001095:Arachidonic Acids; D001549:Benzamides; D048588:Benzoxazines; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011725:Pyridines; D000099252:Fatty Acid Amide Hydrolases; C557973:PF 3845; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C078814:anandamide