In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects

Abstract

BACKGROUND AND PURPOSESince monoacylglycerol lipase (MAGL) has been firmly established as the predominant catabolic enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), a great need has emerged for the development of highly selective MAGL inhibitors. Here, we tested the in vivo effects of one such compound, KML29 (1,1,1,3,3,[1,3]dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate). EXPERIMENTAL APPROACHIn the present study, we tested KML29 in murine inflammatory (i.e. carrageenan) and sciatic nerve injury pain models, as well as the diclofenac-induced gastric haemorrhage model. KML29 was also evaluated for cannabimimetic effects, including measurements of locomotor activity, body temperature, catalepsy, and cannabinoid interoceptive effects in the drug discrimination paradigm. KEY RESULTSKML29 attenuated carrageenan-induced paw oedema and completely reversed carrageenan-induced mechanical allodynia. These effects underwent tolerance after repeated administration of high-dose KML29, which were accompanied by cannabinoid receptor 1 (CB1) receptor desensitization. Acute or repeated KML29 administration increased 2-AG levels and concomitantly reduced arachidonic acid levels, but without elevating anandamide (AEA) levels in the whole brain. Furthermore, KML29 partially reversed allodynia in the sciatic nerve injury model and completely prevented diclofenacinduced gastric haemorrhages. CB1 and CB2 receptors played differential roles in these pharmacological effects of KML29. In contrast, KML29 did not elicit cannabimimetic effects, including catalepsy, hypothermia and hypomotility. Although KML29 did not substitute for Δ 9 -tetrahydrocannabinol (THC) in C57BL/6J mice, it fully and dose-dependantly substituted for AEA in fatty acid amide hydrolase (FAAH) (−/−) mice, consistent with previous work showing that dual FAAH and MAGL inhibition produces THC-like subjective effects. CONCLUSIONS AND IMPLICATIONSThese results indicate that KML29, a highly selective MAGL inhibitor, reduces inflammatory and neuropathic nociceptive behaviour without occurrence of cannabimimetic side effects. LINKED ARTICLESThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx

The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

“…Spinal cords and brains were rapidly harvested, snap-frozen in dry ice, and stored at 280°C until the time of processing. Tissues were further processed according to methods described previously (Ramesh et al, 2011;Ignatowska-Jankowska et al, 2014). See the (Supplemental Material for details.…”

“…We also used the selective receptor antagonists rimonabant, SR144528, and naloxone to examine the respective contributions of CB 1 , CB 2 , and m-opioid receptors in mediating the observed antinociceptive effects. Since significant untoward side effects associated with opioids and cannabinoids could limit therapeutic utility when given in combination, we examined the consequences of dual administration of morphine and MJN110 on gastric motility, to infer opioid-induced constipation (Ross et al, 2008) and cannabimimetic interoceptive effects in mice trained to discriminate the potent cannabinoid receptor agonist CP55,940 from vehicle in the drug discrimination paradigm Walentiny et al, 2013;Ignatowska-Jankowska et al, 2014). Additionally, because the antinociceptive effects of morphine (Cichewicz and Welch, 2003;Smith et al, 2007) and MAGL inhibitors (Schlosburg et al, 2010) undergo tolerance after repeated administration, we examined the consequences of repeated injections of MJN110 and morphine given in combination in the CCI model of neuropathic pain.…”

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

“…intraperitoneal injection without resulting in cannabimimetic side effects including hypomotility, hypothermia and catalepsy. 164 Its administration was accompanied by a dramatic elevation of 2-AG levels and was devoid of alteration of AEA, PEA, OEA levels in mouse brain. In addition, it was shown to alleviate NSAID (e.g.…”

“…diclofenac sodium)-induced gastric injury (haemorrhages) after a 40 kg/mg intraperitoneal injection. Compound 152-induced gastro-protective effects were later identified to be CB1 rather than CB2-dependent, since this protective action was blocked by a CB1 antagonist 131 but not by the CB2 antagonist 1 (3 kg/mg intraperitoneal injection) 164 More recently, compound 152-induced accumulation of 2-AG was revealed to be tissue-dependent. Indeed, the most pronounced elevation of 2-AG levels was observed in the brain and spinal cord.…”

Simplified assays of lipolysis enzymes for drug discovery and specificity assessment of known inhibitors

“…The DAGL ␣ cDNA 2-arachidonoylglycerol, has been implicated in the control of pain mechanisms ( 13 ) and cancer cell proliferation ( 14 ). DAGL enzymes have been found to be important in the production of 2-arachidonoylglycerol and in the control of appetite and pain ( 15 ) and also in the regulation of Ca 2+ infl ux into cells ( 16 ).…”