Contribution of diacylglycerol lipase [beta] to pain after surgery

• Published in: Journal of pain research 2018-01, Vol.11, p.473
• Main Authors: Lu, Yong, Ackermann, Amanda, Luk, Jennifer, Tong, Simon, Puopolo, Michelino, Komatsu, David E, Rebecchi, Mario J, Peng, Xiaoxue, Ojima, Iwao, Kaczocha, Martin, Bogdan, Diane
• Format: Article
• Language: English
• Subjects: Analysis; Arachidonic acid; Central nervous system; COX-2 inhibitors; Criminal investigation; Enzymes; Fatty acids; Ketoprofen; Lipase; Liver; Pain management; Physiological aspects; Postoperative pain; Prostaglandins; Prostaglandins E; Unsaturated fatty acids
• ISSN: 1178-7090; 1178-7090
• DOI: 10.2147/JPR.S157208

Background: Metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG) yields arachidonic acid (AA), the precursor to proalgesic eicosanoids including prostaglandin E2 ([PG[E.sub.2]). Diacylglycerol lipase [beta] (DAGL[beta]) 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 DAGL[beta] produces antinociceptive effects in a model of postoperative pain. Methods: Rats were administered the selective DAGL[beta] 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. Results: Activity-based protein profiling confirmed that KT109 inhibited DAGL[beta] in the lumbar spinal cord (LSC) and brain, confirming that it is a systemically active DAGL[beta] inhibitor. Treatment with KT109 reduced basal 2-AG, AA, and [PG[E.sub.2] levels in the liver but not the brain, indicating that DAGL[beta] activity does not significantly contribute to basal [PG[E.sub.2] production within the central nervous system. Plantar incision elevated the levels of 2-AG and [PG[E.sub.2] in the LSC. Although KT109 did not alter postsurgical 2-AG levels in the LSC, it slightly reduced [PG[E.sub.2] levels. In contrast, the clinically efficacious cyclooxygenase inhibitor ketoprofen completely suppressed [PG[E.sub.2] levels in the LSC. Similarly, KT109 had no significant effect upon postsurgical 2-AG, AA, or [PG[E.sub.2] levels at the incision site, while ketoprofen abolished [PG[E.sub.2] production 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. Conclusion: DAGL[beta] is not the principal enzyme that controls 2-AG derived AA and [PG[E.sub.2] production after surgery, and inhibitors targeting this enzyme are unlikely to be efficacious analgesics superior to those already approved to treat acute postoperative pain. Keywords: pain, incision, surgery, endocannabinoid, 2-AG