Wilkerson_2017_J.Pharmacol.Exp.Ther_363_394

Diacylglycerol lipase (DAGL) alpha and beta, the major biosynthetic enzymes of the endogenous cannabinoid (endocannabinoid) 2-arachidonylglycerol (2-AG), are highly expressed in the nervous system and immune system, respectively. Genetic deletion or pharmacological inhibition of DAGL-beta protects against lipopolysaccharide (LPS)-induced inflammatory responses in mouse peritoneal macrophages and reverses LPS-induced allodynia in mice. To gain insight into the contribution of DAGL-alpha in LPS-induced allodynia, we tested global knockout mice as well as DO34, a dual DAGL-alpha/beta inhibitor. Intraperitoneal administration of DO34 (30 mg/kg) significantly decreased whole-brain levels of 2-AG ( approximately 83%), anandamide ( approximately 42%), and arachidonic acid ( approximately 58%). DO34 dose-dependently reversed mechanical and cold allodynia, and these antinociceptive effects did not undergo tolerance after 6 days of repeated administration. In contrast, DO34 lacked acute thermal antinociceptive, motor, and hypothermal pharmacological effects in naive mice. As previously reported, DAGL-beta (-/-) mice displayed a protective phenotype from LPS-induced allodynia. However, DAGL-alpha (-/-) mice showed full allodynic responses, similar to their wild-type littermates. Interestingly, DO34 (30 mg/kg) fully reversed LPS-induced allodynia in DAGL-alpha (+/+) and (-/-) mice, but did not affect the antinociceptive phenotype of DAGL-beta (-/-) mice in this model, indicating a DAGL-alpha-independent site of action. These findings suggest that DAGL-alpha and DAGL-beta play distinct roles in LPS-induced nociception. Whereas DAGL-alpha appears to be dispensable for the development and expression of LPS-induced nociception, DAGL-beta inhibition represents a promising strategy to treat inflammatory pain.