Endocannabinoid Biosynthesis in Inflammation and Pain

Project Summary In the initial 5 years of this grant, our group has advanced the field of endocannabinoid therapeutics by discovering novel metabolic and signaling functions for the endocannabinoid biosynthetic enzyme DAGLβ in inflammation and pain response. We developed drug delivery strategies for localizing DAGLβ inhibitors to inflammatory sites for potent pain alleviation in preclinical models. We developed phosphoproteomic, chemoproteomic, and lipidomic capabilities to enable biomarker and drug discovery in pain. This renewal application will extend our preclinical investigations of DAGLβ inhibitors as non-opioid analgesics to include kinase activation as a testable mechanism. We will build on the key biological discoveries, productivity, and technological investment of the first funding period to address key gaps in knowledge to probe how disruption of DAGLβ lipid metabolism activates kinase signal transduction, test whether augmented kinase activation can be achieved using new liposomal formulations of DAGLβ inhibitors and uncover the druggable phosphoproteome in inflammatory and neuropathic pain states. We plan to test our central hypothesis that DAGLβ signals through bioenergetic pathways to alter the macrophage phosphoproteome in local inflammatory responses in pain. An improved understanding of endocannabinoid biosynthetic mechanisms in chronic pain states is important for guiding development of non-addictive, targeted analgesics to address the opioid epidemic.