BACKGROUND AND PURPOSE:

Since 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.

EXPERIMENTAL APPROACH:

In 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 hemorrhage 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 RESULTS:

KML29 attenuated carrageenan-induced paw edema and completely reversed carrageenan-induced mechanical allodynia. These effects underwent tolerance after repeated administration of high-dose KML29, which were accompanied by 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 diclofenac-induced gastric hemorrhages. 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 THC in C57BL/6J mice, it fully and dose-dependantly substituted for AEA in FAAH(‱/‱) mice, consistent with previous work showing that dual FAAH and MAGL inhibition produces THC-like subjective effects.

CONCLUSIONS AND IMPLICATIONS:

These results indicate that KML29, a highly selective MAGL inhibitor, reduces inflammatory and neuropathic nociceptive behavior without occurrence of cannabimimetic side effects.
This article is protected by copyright. All rights reserved.

PMID:

 

23848221

 

[PubMed – as supplied by publisher]