title: Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy.
abstract: Distal sensory neuropathies are a hallmark of HIV infections and can result in persistent and disabling pain despite advances in antiretroviral therapies. HIV-sensory neuropathic (HIV-SN) pain may be amenable to cannabinoid treatment, but currently available agonist treatments are limited by untoward side effects and potential for abuse in this patient population. Fatty acid amide hydrolase (FAAH) inhibitors may offer an alternative approach by inhibiting the degradation of endocannabinoids with purportedly fewer untoward CNS side effects. In order to evaluate this potential approach in the management of HIV-SN pain, the recombinant HIV envelope protein gp120 was applied epineurally to the rat sciatic nerve to induce an HIV-SN-like pain syndrome. Two distinct FAAH inhibitory compounds, URB597 and PF-3845 were tested, and contrasted with standard antinociceptive gabapentin or vehicle treatment, for attenuation of tactile allodynia, cold allodynia, and mechanical hyperalgesia. Both FAAH inhibitors markedly reduced cold and tactile allodynia with limited anti-hyperalgesic effects. Peak antinociceptive effects produced by both agents were more modest than gabapentin in reducing tactile allodynia with similar potency ranges. URB597 produced comparable cold anti-allodynic effects to gabapentin, and the effects of both FAAH inhibitors were longer lasting than gabapentin. To assess the contribution of cannabinoid receptors in these antinociceptive effects, CB1 antagonist AM251 or CB2 antagonist SR144528 were tested in conjunction with FAAH inhibitors. Results suggested a contribution of both CB1- and CB2-mediated effects, particularly in reducing tactile allodynia. In summary, these findings support inhibition of endocannabinoid degradation as a promising target for management of disabling persistent HIV-SN pain syndromes.
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Farinaz
authors.initials: F
authors.lastname: Nasirinezhad
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Stanislava
authors.initials: S
authors.lastname: Jergova
authors.affiliation: Ironwood Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Pearson
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: jsagen@miami.edu.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sagen
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000588:Amines / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000077206:Gabapentin; D015699:HIV Envelope Protein gp120; D015658:HIV Infections / Q000503:physiopathology*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000588:Amines; D000700:Analgesics; D001549:Benzamides; D002219:Carbamates; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D000077206:Gabapentin; D015699:HIV Envelope Protein gp120; D010880:Piperidines; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid; D000099252:Fatty Acid Amide Hydrolases; C557973:PF 3845; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
keywords: Allodynia; Antinociception; Endocannabinoid; Gabapentin; HIV neuropathy; Neuropathic pain