Abstract

Diacylglycerol lipase (DAGL) α and β, 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-β protects against lipopolysaccharide (LPS)-induced inflammatory responses in mouse peritoneal macrophages, and reverses LPS-induced allodynia in mice. In order to gain insight into the contribution of DAGL-α in LPS-induced allodynia, we tested global knockout mice as well as DO34, a dual DAGL-α/-β 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 six days of repeated administration. In contrast, DO34 lacked acute thermal antinociceptive, motor, and hypothermal pharmacological effects in naive mice. As previously reported, DAGL-β (-/-) mice displayed a protective phenotype from LPS-induced allodynia. However, DAGL-α (-/-) mice showed full allodynic responses, similar to their wildtype littermates. Interestingly, DO34 (30 mg/kg) fully reversed LPS-induced allodynia in DAGL-α (+/+) and (-/-) mice, but did not affect the antinociceptive phenotype of DAGL-β (-/-) mice in this model, indicating a DAGL-α independent site of action. These findings suggest that DAGL-α and -β play distinct roles in LPS-induced nociception. Whereas DAGL-α appears to be dispensable for the development and expression of LPS-induced nociception, DAGL-β inhibition represents a promising strategy to treat inflammatory pain.