Peripheral antinociceptive effects of inhibitors of monoacylglycerol lipase in a rat model of inflammatory pain

Abstract

The endocannabinoid 2-arachidonoylglycerol (2-AG) is degraded primarily by monoacylglycerol lipase (MGL). We compared peripheral antinociceptive effects of JZL184, a novel irreversible MGL inhibitor, with the reversible MGL-preferring inhibitor URB602 and exogenous 2-AG in rats. EXPERIMENTAL APPROACHNociception in the formalin test was assessed in groups receiving dorsal paw injections of vehicle, JZL184 (0.001-300 mg), URB602 (0.001-600 mg), 2-AG (ED50), 2-AG + JZL184 (at their ED50), 2-AG + URB602 (at their ED50), AM251 (80 mg), AM251 + JZL184 (10 mg), AM630 (25 mg) or AM630 + JZL184 (10 mg). Effects of MGL inhibitors on endocannabinoid accumulation and on activities of endocannabinoid-metabolizing enzymes were assessed. KEY RESULTSIntra-paw administration of JZL184, URB602 and 2-AG suppressed early and late phases of formalin pain. JZL184 and URB602 acted through a common mechanism. JZL184 (ED50 Phase 1: 0.06 Ϯ 0.028; Phase 2: 0.03 Ϯ 0.011 mg) produced greater antinociception than URB602 (ED50 Phase 1: 120 Ϯ 51.3; Phase 2: 66 Ϯ 23.9 mg) or 2-AG. Both MGL inhibitors produced additive antinociceptive effects when combined with 2-AG. Antinociceptive effects of JZL184, like those of URB602, were blocked by cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) antagonists. JZL184 suppressed MGL but not fatty-acid amide hydrolase or N-arachidonoyl-phosphatidylethanolamine phospholipase D activities ex vivo. URB602 increased hind paw 2-AG without altering anandamide levels. CONCLUSIONS AND IMPLICATIONSMGL inhibitors suppressed formalin-induced pain through peripheral CB1 and CB2 receptor mechanisms. MGL inhibition increased paw skin 2-AG accumulation to mediate these effects. MGL represents a target for the treatment of inflammatory pain.

Chemical Probes of Endocannabinoid Metabolism

“…Despite their relatively recent development, chemical tools that selectively inactivate MAGL in vivo have already demonstrated efficacy in multiple preclinical pain paradigms (Hohmann et al, 2005;Kinsey et al, 2009Kinsey et al, , 2010Long et al, 2009a,c;Schlosburg et al, 2010;BusquetsGarcia et al, 2011;Guindon et al, 2011Guindon et al, , 2013Khasabova et al, 2011;Ghosh et al, 2012). Not only have these studies implicated MAGL as an additional therapeutic target for the treatment of pain, they have revealed mechanistic differences between anandamide and 2-AG-mediated antinociception.…”

“…URB602's relatively weak potency complicates its systemic administration in vivo and its selectivity is a matter of debate because it has been shown to be equally potent against FAAH in vitro (Muccioli et al, 2007;Vandevoorde et al, 2007). However, URB602 administration has been shown to attenuate nociception in rodent models of acute, inflammatory, and neuropathic pain (Comelli et al, 2007;Guindon et al, 2007Guindon et al, , 2011Desroches et al, 2008).…”

“…URB597-mediated effects were blocked by CB1 antagonists, whereas JZL184-induced antinociception was prevented by CB1 and CB2 antagonists. CB1 and CB2 receptors also mediated the antinociceptive effects of local MAGL inhibition in the formalin test in rats (Guindon et al, 2011) and the anti-allodynic effects of systemic MAGL blockade in mice (Ghosh et al, 2012). Peripheral blockade of FAAH (URB597, 9 mg i.p.l.)…”

Dynamic changes to the endocannabinoid system in models of chronic pain

“…10-fold) in rat brain membranes [92], but a small number of reports detailing the antinociceptive efficacy of local administration of JZL184 in the rat have been published. Indeed, antinociceptive effects of intra-plantar administration of JZL184 have been described in both phases of the formalin model of inflammatory pain [94], and also in capsaicin-induced acute pain [95], with mechanisms involving both CB1 and CB2 receptors. The effects of spinal or supra-spinal administration of JZL184 on nociceptive processing in control rats, or in models of chronic pain have yet to be reported.…”

Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications

“…Like inhibitors of FAAH, MAG lipase inhibitors display antinociceptive activity in a number of different animal models that for one or more of these compounds include models of acute, visceral, inflammatory, neuropathic and/or bone cancer pain (4,13,(20)(21)(22)43,(53)(54)(55)(56)(57) . There is evidence too, that in rats, MAG lipase inhibitors can reduce signs of inflammatory pain not only when administered systemically but also when injected directly into the spinal cord or inflamed hind paws (58)(59)(60) . Moreover, results obtained from animal experiments with JZL184 suggest that, like FAAH inhibitors, MAG lipase inhibitors have several other potential therapeutic applications (Table 2).…”