PT  - JOURNAL ARTICLE
AU  - Wilkerson, Jenny L.
AU  - Donvito, Giulia
AU  - Grim, Travis W.
AU  - Abdullah, Rehab A.
AU  - Ogasawara, Daisuke
AU  - Cravatt, Benjamin F.
AU  - Lichtman, Aron H.
TI  - Investigation of Diacylglycerol Lipase Alpha Inhibition in the Mouse Lipopolysaccharide Inflammatory Pain Model
AID  - 10.1124/jpet.117.243808
DP  - 2017 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 394--401
VI  - 363
IP  - 3
4099  - http://jpet.aspetjournals.org/content/363/3/394.short
4100  - http://jpet.aspetjournals.org/content/363/3/394.full
SO  - J Pharmacol Exp Ther2017 Dec 01; 363
AB  - 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. 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 6 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 wild-type 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 DAGL-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.