Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models

Abstract

1 While cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central CB 1 receptor-mediated motor and psychotropic side effects. The actions of endocannabinoids, such as anandamide are terminated by removal from the extracellular space, then subsequent enzymatic degradation by fatty-acid amide hydrolase (FAAH). In the present study, we compared the effect of a selective FAAH inhibitor, URB597, to that of a pan-cannabinoid receptor agonist HU210 in rat models of chronic inflammatory and neuropathic pain. 2 Systemic administration of URB597 (0.3 mg kg À1 ) and HU210 (0.03 mg kg À1 ) both reduced the mechanical allodynia and thermal hyperalgesia in the CFA model of inflammatory pain. In contrast, HU210, but not URB597, reduced mechanical allodynia in the partial sciatic nerve-ligation model of neuropathic pain. HU210, but not URB597, produced a reduction in motor performance in unoperated rats. 3 The effects of URB597 in the CFA model were dose dependent and were reduced by coadministration with the cannabinoid CB 1 antagonist AM251 (1 mg kg À1 ), or the CB 2 and SR144528 (1 mg kg À1 ). Coadministration with AM251 plus SR144528 completely reversed the effects of URB597. 4 These findings suggest that the FAAH inhibitor URB597 produces cannabinoid CB 1 and CB 2 receptor-mediated analgesia in inflammatory pain states, without causing the undesirable side effects associated with cannabinoid receptor activation.

Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid

“…Inhibition of FAAH by URB597 does not affect motor function or induce psychotropic effects such as those associated with exogenously applied CB1 agonists (Jayamanne et al, 2006). The lack of a significant effect exhibited by URB597 on baseline neuronal activity, while producing a profound reduction in KAevoked firing, suggests that inhibition of elevated neuronal activity via FAAH inhibition may have therapeutic relevance for conditions such as epilepsy.…”

Endocannabinoid system and pain: an introduction

“…Further studies have therefore focused on the use of FAAH and MAGL inhibitors to prolong the effects of endogenous EC actions. Systemic inactivation of FAAH via compounds such as URB597, OL135 and PF-3845 has been shown to be anti-nociceptive in models of acute and inflammatory pain (75)(76)(77)(78)(79)(80) . Elevations in both AEA and 2-AG have been shown, as well as reduced carrageenan-induced hyperalgesia (81) and expansion of peripheral receptive field size of wide dynamic range neurons (a marker of central sensitisation) following intra-plantar URB597 (82) .…”

The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors

“…The presumption that electronwithdrawing groups in para-position on the phenyl ring would increase the electrophilicity of the carbonyl carbon prompted us to prepare a series of N-alkyl carbamates with various electron-withdrawing and electron-donating substituents (Table 4). Methoxy carbonyl (30)(31)(32)(33), nitro (34)(35)(36), cyano (37 and 38), and bromine (39) were selected as electron-withdrawing (EWG), and methoxy (40) and methyl (41) as electron-donating groups (EDG). The neutral effect was evaluated with the unsubstituted O-phenyl carbamates 42 and 43.…”

“…Probably, the most well-studied FAAH inhibitors are the carbamate-based 3 0 -carbamoylbiphenyl-3-yl ester (4, URB597) ( Fig. 2) [21,29] and the a-keto heterocycle-based 7-phenyl-1-(5-(pyridin-2-yl)oxazol-2-yl)heptan-1-one (OL-135) [19], which have gained considerable promise for treating anxiety, inflammation, and pain [7,19,[29][30][31].…”