The Novel Reversible Fatty Acid Amide Hydrolase Inhibitor ST4070 Increases Endocannabinoid Brain Levels and Counteracts Neuropathic Pain in Different Animal Models

Caprioli, A. and Coccurello, R. and Rapino, C. and Di Serio, S. and Di Tommaso, M. and Vertechy, M. and Vacca, V. and Battista, N. and Pavone, F. and Maccarrone, M. and Borsini, F. (2012) The Novel Reversible Fatty Acid Amide Hydrolase Inhibitor ST4070 Increases Endocannabinoid Brain Levels and Counteracts Neuropathic Pain in Different Animal Models. Journal of Pharmacology and Experimental Therapeutics, 342 (1). pp. 188-195. ISSN 1521-0103

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Abstract

The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine- 1-carboxylate (ST4070), a novel reversible inhibitor of fatty acid amide hydrolase (FAAH), was investigated for acute pain sensitivity and neuropathic pain in rats and mice. Brain enzymatic activity of FAAH and the endogenous levels of its substrates, anandamide (AEA; Narachidonoylethanolamine), 2-arachidonoylglycerol (2-AG), and Npalmitoylethanolamine (PEA), were measured in control and ST4070- treated mice. ST4070 (10, 30, and 100 mg/kg) was orally administered to assess mechanical nociceptive thresholds and allodynia by using the Randall-Selitto and von Frey tests, respectively. Neuropathy was induced in rats by either the chemotherapeutic agent vincristine or streptozotocin-induced diabetes, whereas the chronic constriction injury (CCI) model was chosen to evaluate neuropathy in mice. ST4070 produced a significant increase of nociceptive threshold in rats and counteracted the decrease of nociceptive threshold in the three distinct models of neuropathic pain. In diabetic mice, ST4070 inhibited FAAH activity and increased the brain levels of AEA and PEA, without affecting that of 2-AG. The administration of ST4070 generated long-lasting pain relief compared with pregabalin and the FAAH inhibitors 1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL135) and cyclohexylcarbamic acid 3�-carbamoylbiphenyl-3- ylester (URB597) in CCI neuropathic mice. The antiallodynic effects of ST4070 were prevented by pretreatment with cannabinoid type 1 and cannabinoid type 2 receptor antagonists and by the selective peroxisome proliferator-activated receptor � antagonist [(2S)-2- [[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl- ]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl- ]propyl]-carbamic acid ethyl ester (GW6471). The administration of ST4070 generated long-lasting neuropathic pain relief compared with pregabalin and the FAAH inhibitors OL135 and URB597. Taken together, the reversible FAAH inhibitor ST4070 seems to be a promising nove

Item Type:	Article
Subjects:	500 Scienze naturali e Matematica 500 Scienze naturali e Matematica > 570 Scienze della vita; Biologia
Depositing User:	PhD Roberto Coccurello
Date Deposited:	19 Dec 2016 13:46
Last Modified:	19 Dec 2016 13:46
URI:	http://eprints.bice.rm.cnr.it/id/eprint/15478

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