The Identification of novel pharmacological approaches to reduce pain is critical from public health perspective. One of the most common reasons to seek medical attention is that of pain, and collectively pain represents a huge financial burden to society. Once thought to be only mediated solely by neuronal firing, the immune system has been revealed to play a critical role in the regulation, maintenance and transition from acute to chronic pain states. One class that has broad immune relevance during periods of pain is the prostaglandins. Recent discoveries yield insight on a novel pathway of diacylglycerol lipase (DAGL) involvement in the ultimate formation of arachidonic acid, which can then be transformed into prostaglandins. In vitro work shows that inhibiting DAGL-?, one form of DAGL, reduces the biosynthesis of 2-arachidonyl glycerol, the endocannabinoid ligand and a precursor of arachidonic acid. This reduction in free arachidonic acid in turn, results in decreases in the formation of the prostaglandin PGE2 and the pro-inflammatory cytokine tumor necrosis factor- alpha (TNF-?). Therefore, we hypothesize that pharmacological inhibition of DAGL-? with a novel compound, KT109, in mice will lower pro-inflammatory cytokines, prostaglandins and other inflammatory mediators of pain, leading to reversal of behaviors associated with pain. Accordingly, the objectives of this training plan are to characterize the ant-pain effects of DAGL-? inhibitors in murine pain models and determine the underlying in vivo mechanism(s) of action of this class of compounds. The proposed aims to examine these objectives are: 1.) Aim 1: Elucidate the consequences of blocking DAGL- ? in inflammatory pain assays. 2.) Determine the locus of action mediating the pain stimulated and pain depressed behavioral effects of DAGL-? inhibitors in the LPS model of inflammatory pain. 3.) Determine the effects of DAGL-? inhibition on pro-inflammatory and pain mediators. Under these aims the consequences of inhibiting DAGL-? will be investigated in the LPS inflammatory pain model, and the importance of prostaglandins and other pro-inflammatory mediators will be identified. This work aiming to identify a novel mechanism of prostaglandin regulation and subsequent pain control will provide a critical training plan for Dr. Wilkerson to gain the necessary bench skills and conceptual framework to become an independent investigator in developing analgesics that lack abuse potential. Ultimately, the knowledge obtained from this research has the potential to establish DAGL-? as a target linking upstream prostaglandin control to pain relief.
Inflammatory modulation has proven to be a major component in states of pain. While targeting some inflammatory mediators has been useful in the current treatments, a need persists for better therapeutics. This research provides a novel pathway of how inhibiting the enzyme DAGL-? may contribute to pain relief.
