Investigation of Diacylglycerol Lipase Alpha Inhibition in the Mouse Lipopolysaccharide Inflammatory Pain Model.

Diacylglycerol lipase (DAGL) and , 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- 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- in LPS-induced allodynia, we tested global knockout mice as well as DO34, a dual DAGL-/ inhibitor. Intraperitoneal administration of DO34 (30 mg/kg) significantly decreased whole-brain levels of 2-AG (∼83%), anandamide (∼42%), and arachidonic acid (∼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- (-/-) mice displayed a protective phenotype from LPS-induced allodynia. However, DAGL- (-/-) mice showed full allodynic responses, similar to their wild-type littermates. Interestingly, DO34 (30 mg/kg) fully reversed LPS-induced allodynia in DAGL- (+/+) and (-/-) mice, but did not affect the antinociceptive phenotype of DAGL- (-/-) mice in this model, indicating a DAGL--independent site of action. These findings suggest that DAGL- and DAGL- play distinct roles in LPS-induced nociception. Whereas DAGL- appears to be dispensable for the development and expression of LPS-induced nociception, DAGL- inhibition represents a promising strategy to treat inflammatory pain.