Repeated Low-Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains Cannabinoid Receptor Type 1–Mediated Antinociceptive and Gastroprotective Effects

Abstract

The monoacylglycerol lipase (MAGL) inhibitor 4-nitrophenyl 4-(dibenzo [d] [1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) produces antinociceptive and anti-inflammatory effects. However, repeated administration of high-dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, crosstolerance to the pharmacological effects of cannabinoid receptor agonists, and cannabinoid receptor type 1 (CB 1 ) downregulation and desensitization. This functional CB 1 receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low-dose JZL184 maintains its antinociceptive actions in the chronic constriction injury of the sciatic nerve neuropathic pain model and protective effects in a model of nonsteroidal anti-inflammatory drug-induced gastric hemorrhages. Mice given daily injections of high-dose JZL184 ($16 mg/kg) for 6 days displayed decreased CB 1 receptor density and function in the brain, as assessed in 35 S]thio)triphosphate binding assays, respectively. In contrast, normal CB 1 receptor expression and function were maintained following repeated administration of low-dose JZL184 (#8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high-dose JZL184 underwent tolerance following repeated administration, but these effects were maintained following repeated low-dose JZL184 treatment. Consistent with these observations, repeated high-dose JZL184, but not repeated low-dose JZL184, elicited cross-tolerance to the common pharmacological effects of D 9-tetrahydrocannabinol. This same pattern of effects was found in a rimonabant [(5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)]-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional CB 1 receptor tachyphylaxis/tolerance or cannabinoid dependence.

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

“…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).…”

“…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). Indeed, JZL184 and combo treatments induced a statistically significant higher increase in 2-AG level in controls as compared with CUS animals ( Figure 5).…”

“…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.…”

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

“…These adverse effects following high-dose 151 treatment might be attributed to its off-target inhibition of FAAH, consistent with the previous finding that dual FAAH/MAGL inhibition produced cannabimimetic side effects. 159,160 Furthermore, the administration of 151 was demonstrated to produce gastroprotective and antidepressant-like effects post a 4 mg/kg intraperitoneal injection. 160,161 The determination of the binding mechanism indicated that 151 covalently and irreversibly bound to MAGL through the formation of the carbamylated-enzyme adduct ( Figure 56).…”

Activation of platelets by endocannabinoids: Distinct agonists or arachidonate reservoirs?

“…Against this background, here I would like to make a warning that selective inhibitors like JZL184 (especially if used at quite high concentrations) might hit unexpected offtargets that significantly contribute to the biological activity of eCBs. Incidentally, besides potentially unknown off-targets JZL184 inhibits FAAH with an IC 50 of 4 mM, and can affect CB 1 -dependent signaling through down-regulation and desensitization of this receptor [11]. Another major point that I would like to make is that eCBs have been clearly demonstrated to be good substrates for the key-enzymes responsible for the classical arachidonate cascade (i.e., cyclooxygenases and lipoxygenases), leading to the generation of oxygenated derivatives endowed with distinct biological activities [12].…”