The monoacylglycerol lipase inhibitor JZL184 suppresses inflammatory pain in the mouse carrageenan model

Abstract

Aim The present study tested whether the selective monoacylglycerol lipase (MAGL) inhibitor JZL184 would reduce allodynia and paw edema in the carrageenan test. Main methods The anti-edematous and anti-allodynic effects of JZL184 were compared to those of PF-3845, an inhibitor of fatty acid amide hydrolase (FAAH), and diclofenac, a non-selective cyclooxygenase inhibitor. Cannabinoid receptor involvement in the anti-edematous and anti-allodynic effects of JZL184 was evaluated by administration of the respective CB1 and CB2 receptor antagonists rimonabant and SR144528 as well as with CB1(−/−) and CB2(−/−) mice. JZL184 (1.6, 4, 16, or 40 mg/kg) was administered for six days to assess tolerance. Key findings JZL184 administered before or after carrageenan significantly attenuated carrageenan-induced paw edema and mechanical allodynia. Complementary genetic and pharmacological approaches revealed that the anti-allodynic effects of JZL184 required both CB1 and CB2 receptors, but only CB2 receptors mediated its anti-edematous actions. Importantly, both the anti-edematous and anti-allodynic effects underwent tolerance following repeated injections of high dose JZL184 (16 or 40 mg/kg), but repeated administration of low dose JZL184 (4 mg/kg) retained efficacy. Significance These results suggest that the MAGL inhibitor JZL184 reduces inflammatory nociception through the activation of both CB1 and CB2 receptors, with no evidence of tolerance following repeated administration of low doses.

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

“…The ECS has important roles in both psychiatric disorders (Lutz, 2009;Hill and Patel, 2013) and pain states (Kinsey et al, 2009Piomelli et al, 2006;Piomelli and Sasso, 2014). The anxiolytic and analgesic properties of inhibitors of FAAH and MAGL have been extensively described (Kathuria et al, 2003;Jhaveri et al, 2006;Rossi et al, 2010;Sciolino et al, 2011;Ghosh et al, 2013;Kinsey et al, 2013). Therefore, targeting the ECS may represent a therapeutic strategy, particularly for the treatment of chronic pain associated with emotional imbalance.…”

Chemical Probes of Endocannabinoid Metabolism

“…or MAGL (JZL184, 40 mg/kg i.p.) inhibition, resulting in maximal endocannabinoid elevations (.10-fold), produced antinociceptive effects of similar magnitude in tests of acute thermal pain, visceral pain, neuropathic pain, and inflammatory pain, despite the fact that anandamide and 2-AG are present in the brain at dramatically different basal levels (Kinsey et al, 2009Long et al, 2009c;Schlosburg et al, 2010;Ghosh et al, 2012).…”

“…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.…”

Dynamic changes to the endocannabinoid system in models of chronic pain

“…These effects were accompanied by a loss of JZL184-mediated analgesia, and cross tolerance to the antinociceptive and hypothermic effects of the CB1 receptor agonist WIN55,212,2. The development of analgesic tolerance to chronic JZL184 may be overcome, however, as repeated treatment with submaximal doses of JZL184 (,8 mg kg 21 ) produced sustained analgesic effects [100]. Although these data suggest that MAGL inhibition has therapeutic potential for the treatment of pain, the demonstration that chronic JZL184 administration precipitated withdrawal responses to rimonabant, as indicated by an increase in paw flutters [101], suggests that prolonged JZL184 treatment may be associated with physical dependence.…”