Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain.
Cannabinoid-based medicines have therapeutic potential for the treatment of pain. Augmentation of levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is analgesic in models of acute and inflammatory pain states. The aim of this study was to determine whether local inhibition of FAAH alters nociceptive responses of spinal neurons in the spinal nerve ligation model of neuropathic pain. Electrophysiological studies were performed 14-18 d after spinal nerve ligation or sham surgery, and the effects of the FAAH inhibitor cyclohexylcarbamic acid 3-carbamoyl biphenyl-3-yl ester (URB597) on mechanically evoked responses of spinal neurons and levels of endocannabinoids were determined. Intraplantar URB597 (25 microg in 50 microl) significantly (p < 0.01) attenuated mechanically evoked responses of spinal neurons in sham-operated rats. Effects of URB597 were blocked by the cannabinoid 1 receptor (CB1) antagonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide] (30 microg in 50 microl) and the opioid receptor antagonist naloxone. URB597 treatment increased levels of anandamide, 2-arachidonyl glycerol, and oleoyl ethanolamide in the ipsilateral hindpaw of sham-operated rats. Intraplantar URB597 (25 microg in 50 microl) did not, however, alter mechanically evoked responses of spinal neurons in spinal nerve ligated (SNL) rats or hindpaw levels of endocannabinoids. Intraplantar injection of a higher dose of URB597 (100 microg in 50 microl) significantly (p < 0.05) attenuated evoked responses of spinal neurons in SNL rats but did not alter hindpaw levels of endocannabinoids. Spinal administration of URB597 attenuated evoked responses of spinal neurons and elevated levels of endocannabinoids in sham-operated and SNL rats. These data suggest that peripheral FAAH activity may be altered or that alternative pathways of metabolism have greater importance in SNL rats.
Jhaveri
Maulik D
MD
School of Biomedical Sciences, Medical School, Queens Medical Centre, University of Nottingham, Nottinghamshire NG7 2UH, United Kingdom. maulik.jhaveri@nottingham.ac.uk
Richardson
Denise
D
Kendall
David A
DA
Barrett
David A
DA
Chapman
Victoria
V
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000627:therapeutic use; D002219:Carbamates / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D007278:Injections, Spinal; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000201:enzymology*; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D001549:Benzamides; D002219:Carbamates; D004791:Enzyme Inhibitors; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester