Jennifer Luk, Yong Lu, Amanda Ackermann, Xiaoxue Peng, Diane Bogdan, Michelino Puopolo, David E Komatsu, Simon Tong, Iwao Ojima, Mario J Rebecchi, Martin Kaczocha

Metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG) yields arachidonic acid (AA), the precursor to proalgesic eicosanoids including prostaglandin E2 (PGE2). Diacylglycerol lipase β (DAGLβ) is an enzyme that synthesizes 2-AG and its inhibition reduces eicosanoid levels and produces antinociceptive effects in models of inflammatory pain. Here we test whether inhibition of DAGLβ produces antinociceptive effects in a model of postoperative pain. Rats were administered the selective DAGLβ inhibitor KT109 or vehicle and underwent plantar incision. Postsurgical pain/disability was examined using evoked (mechanical hyperalgesia), functional (incapacitance/weight bearing), and functional/spontaneous (locomotion) modalities. Activity-based protein profiling confirmed that KT109 inhibited DAGLβ in the lumbar spinal cord (LSC) and brain, confirming that it is a systemically active DAGLβ inhibitor. Treatment with KT109 reduced basal 2-AG, AA, and PGE2levels in the liver but not the brain, indicating that DAGLβ activity does not significantly contribute to basal PGE2production within the central nervous system. Plantar incision elevated the levels of 2-AG and PGE2in the LSC. Although KT109 did not alter postsurgical 2-AG levels in the LSC, it slightly reduced PGE2levels. In contrast, the clinically efficacious cyclooxygenase inhibitor ketoprofen completely suppressed PGE2levels in the LSC. Similarly, KT109 had no significant effect upon postsurgical 2-AG, AA, or PGE2levels at the incision site, while ketoprofen abolished PGE2production at this location. KT109 and ketoprofen reversed the weight bearing imbalance induced by plantar incision, yet neither KT109 nor ketoprofen had any significant effect on mechanical hyperalgesia. Treatment with ketoprofen partially but significantly rescued the locomotor deficit induced by incision while KT109 was without effect. DAGLβ is not the principal enzyme that controls 2-AG derived AA and PGE2production after surgery, and inhibitors targeting this enzyme are unlikely to be efficacious analgesics superior to those already approved to treat acute postoperative pain.