Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system

Abstract

Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. Here we show that a similar form of functional antagonism is produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to cannabinoid receptor (CB1) agonists in mice, effects that were phenocopied by genetic disruption of MAGL. Chronic MAGL blockade also caused physical dependence, impaired endocannabinoid-dependent synaptic plasticity, and desensitization of brain CB1 receptors. These data contrasted with blockade of fatty acid amide hydrolase (FAAH), an enzyme that degrades the other major endocannabinoid anandamide, which produced sustained analgesia without impairing CB1 receptors. Thus, individual endocannabinoids generate distinct analgesic profiles that are either sustained or transitory and associated with agonism and functional antagonism of the brain cannabinoid system, respectively.

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

“…This suggests that an increase in 2-AG rather than AEA levels is responsible for these behaviors and indicates differential roles of these two eCBs in brain functions (Gorzalka et al, 2008;Pan et al, 2009). The anxiogenic and depression-like effects observed in the control mice cannot be related to the dosage of JZL184, as the dose used here (8 mg/kg/day) did not induce cannabimimetic effects, in agreement with previous works (Long et al, 2009a;Schlosburg et al, 2010;Wise et al, 2012). The moderate dose employed here should also be devoid of the decreased CB1 receptor function observed at high doses of the drug (Schlosburg et al, 2010;Kinsey et al, 2013), although, differently from these previous reports, in our case the duration of the treatment was longer.…”

“…The anxiogenic and depression-like effects observed in the control mice cannot be related to the dosage of JZL184, as the dose used here (8 mg/kg/day) did not induce cannabimimetic effects, in agreement with previous works (Long et al, 2009a;Schlosburg et al, 2010;Wise et al, 2012). The moderate dose employed here should also be devoid of the decreased CB1 receptor function observed at high doses of the drug (Schlosburg et al, 2010;Kinsey et al, 2013), although, differently from these previous reports, in our case the duration of the treatment was longer. As JZL184-induced increase in 2-AG levels is dependent on the dose as well as the duration of the treatment (Kinsey et al, 2013), one possibility is that in healthy mice (controls) chronic administration of JZL184 may have exacerbated the 2-AG-signaling, along with an eventual loss of MAGL activity-dependent neuroprotective mechanisms (Nomura et al, 2011), to an extent sufficient to produce the behavioral responses observed, and which usually occur at high doses of CB1 receptor agonists (Rey et al, 2012).…”

Dual Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Blockade Produces THC-Like Morris Water Maze Deficits in Mice

“…Previous studies have found that genetic deletion of FAAH leads to 10-fold increases in whole brain AEA levels 1 and that treatment with 16 or 40 mg/ kg JZL184 produces approximately 7−8-fold increases in levels of 2-AG in whole brains. 18,19,37 The present results extend these findings by revealing increases in AEA and 2-AG levels in specific brain regions. CB 1 receptor activation by exogenously applied cannabinoids, such as THC, lacks the regional selectivity and rapid metabolism of endocannabinoids.…”

RETRACTED ARTICLE: Cannabinoid Type 1 Receptor Availability in the Amygdala Mediates Threat Processing in Trauma Survivors

“…Emerging evidence supports the potential utility of such targets, suggesting that variation in the FAAH gene is linked to reduced expression of FAAH that consequently results in elevations in circulating levels of anadamide (Chiang et al, 2004;Sipe et al, 2010), as well as decreased amygdala response to threat (Hariri et al, 2009) and more rapid habituation of the amygdala to repeated threat (Gunduz-Cinar et al, 2013b). Notably, elevating anandamide levels via FAAH inhibition appear to provide a more circumscribed spectrum of behavioral effects than blocking MAGL (Blankman and Cravatt, 2013) that could potentially result in a more beneficial side effect profile, as anandamide is less prone to CB 1 receptor desensitization and resultant behavioral tolerance (Lichtman et al, 2002;Schlosburg et al, 2010). These classes of compounds are currently being investigated for their potential efficacy in treating mood and anxiety disorders.…”