Blockade of Endocannabinoid-Degrading Enzymes Attenuates Neuropathic Pain

Abstract

Direct-acting cannabinoid receptor agonists are well known to reduce hyperalgesic responses and allodynia after nerve injury, although their psychoactive side effects have damped enthusiasm for their therapeutic development. Alternatively, inhibiting fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the principal enzymes responsible for the degradation of the respective endogenous cannabinoids, anandamide (AEA) and 2-arachydonylglycerol (2-AG), reduce nociception in a variety of nociceptive assays, with no or minimal behavioral effects. In the present study we tested whether inhibition of these enzymes attenuates mechanical allodynia, and acetone-induced cold allodynia in mice subjected to chronic constriction injury of the sciatic nerve. Acute administration of the irreversible FAAH inhibitor, cyclohexylcarbamic acid 3Ј-carbamoylbiphenyl-3-yl ester (URB597), or the reversible FAAH inhibitor, 1-oxo-1-[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL-135), decreased allodynia in both tests. This attenuation was completely blocked by pretreatment with either CB 1 or CB 2 receptor antagonists, but not by the TRPV1 receptor antagonist, capsazepine, or the opioid receptor antagonist, naltrexone. The novel MAGL inhibitor, 4-nitrophenyl 4-(dibenzo [d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) also attenuated mechanical and cold allodynia via a CB 1 , but not a CB 2 , receptor mechanism of action. Whereas URB597 did not elicit antiallodynic effects in FAAH(Ϫ/Ϫ) mice, the effects of JZL184 were FAAH-independent. Finally, URB597 increased brain and spinal cord AEA levels, whereas JZL184 increased 2-AG levels in these tissues, but no differences in either endocannabinoid were found between nerve-injured and control mice. These data indicate that inhibition of FAAH and MAGL reduces neuropathic pain through distinct receptor mechanisms of action and present viable targets for the development of analgesic therapeutics.Although cannabis has been used for thousands of years to treat pain and other ailments, its undesirable psychomimetic effects have dampened enthusiasm for further drug development. Instead, recent research has focused on targeting the endogenous cannabinoid system for the development of new analgesics ). The endogenous cannabinoid system consists of two cloned cannabinoid receptors (CB 1 and CB 2 ), various proposed endocannabinoid ligands, including anandamide (AEA; Devane et al., 1992) and 2-arachidonylglycerol (2-AG; Mechoulam et al., 1995), and the enzymes that regulate the biosynthesis and catabolism of the endocannabinoids. In particular, fatty acid amide hydrolase (FAAH;Cravatt et al., 1996) and monoacylglycerol lipase (MAGL;Blankman et al., 2007) are the primary catabolic enzymes of AEA and 2-AG, respectively.

Global deletion of MGL in mice delays lipid absorption and alters energy homeostasis and diet-induced obesity

“…The potent MGL inhibitor, JZL184, causes 8-fold increases in brain 2-AG levels and cannabimimetic behavioral effects in mice, such as analgesia, hypolocomotion, catalepsy, and hypothermia, the so-called CB tetrad ( 8,31 ). Interestingly, however, in contrast to acute 2-AG elevation, prolonged 2-AG elevation following chronic administration of JZL184 results in desensitization of the central EC system, likely caused by tonic activation of CB1 (32)(33)(34).…”

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).…”

Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6

“…The endocannabinoid 2-arachidonoylglycerol (2-AG) is involved in various (patho)physiological processes and exerts numerous beneficial actions (ranging from pain modulation to reduction of anxiety) (5)(6)(7)(8)(9)(10)(11). The activity of this bioactive lipid depends on its endogenous levels, tightly controlled by the 2-AG hydrolyzing enzymes (12).…”