Endocannabinoid and Prostanoid Crosstalk in Pain

The eCB and PG systems have been studied separately for a long time. Increasing evidence has revealed a strong connection between the two systems, supporting a change in paradigm whereby both systems are studied together. eCBs and PGs are key players in nociception, acting via peripheral, spinal, and supraspinal mechanisms. As we suggest here, targeting multiple enzymes and receptors will represent new opportunities to treat pain, using the cooperative effects of modulating both the eCB and prostanoid systems. Increasing evidence supports the bioactivity of PG-EA and PG-Gs, including in inflammatory and painful situations. Interfering with endocannabinoid (eCB) metabolism to increase their levels is a proven anti-nociception strategy. However, because the eCB and prostanoid systems are intertwined, interfering with eCB metabolism will affect the prostanoid system and inversely. Key to this connection is the production of the cyclooxygenase (COX) substrate arachidonic acid upon eCB hydrolysis as well as the ability of COX to metabolize the eCBs anandamide (AEA) and 2-arachidonoylglycerol (2-AG) into prostaglandin-ethanolamides (PG-EA) and prostaglandin-glycerol esters (PG-G), respectively. Recent studies shed light on the role of PG-Gs and PG-EAs in nociception and inflammation. Here, we discuss the role of these complex systems in nociception and new opportunities to alleviate pain by interacting with them. Interfering with endocannabinoid (eCB) metabolism to increase their levels is a proven anti-nociception strategy. However, because the eCB and prostanoid systems are intertwined, interfering with eCB metabolism will affect the prostanoid system and inversely. Key to this connection is the production of the cyclooxygenase (COX) substrate arachidonic acid upon eCB hydrolysis as well as the ability of COX to metabolize the eCBs anandamide (AEA) and 2-arachidonoylglycerol (2-AG) into prostaglandin-ethanolamides (PG-EA) and prostaglandin-glycerol esters (PG-G), respectively. Recent studies shed light on the role of PG-Gs and PG-EAs in nociception and inflammation. Here, we discuss the role of these complex systems in nociception and new opportunities to alleviate pain by interacting with them. a lipid is considered bioactive when variation in its levels leads to functional consequences through the activation of receptors as opposed to simply a source of energy or a structural cell component. the first relay of primary afferent fibers from muscles, skin, and viscera. It is a bilateral structure situated on the dorsolateral side of the spinal cord and is part of the gray matter. This structure is also actively involved in the processing of nociceptive signals because it is the region where the descending pain pathway modulates inputs from the periphery. anatomical structures regrouping the cell bodies of pseudounipolar neurons that relay peripheral sensory signals to the spinal cord. They are located in the intervertebral foramina. lipid mediators that bind to and activate the cannabinoid receptors (CB1 and CB2). Thus, a bona fide eCB should be endogenously produced and bind at least one of the two cannabinoid receptors. increased pain arising from stimuli that normally evoke pain. esters of a fatty acid with glycerol. 2-Arachidonoylglycerol is an eCB monoacylglycerol. 2-Palmitoylglycerol and 2-oleoylglycerol (a ligand for the GPR119 receptor) are examples of monoacylglycerols not binding the cannabinoid receptors. Monoacylglycerols are produced from diacylglycerols via the action of DAGL α or β. amides of a fatty acid and ethanolamine. AEA is an eCB, while PEA and N-oleoylethanolamine (OEA) are two examples of NAEs that do not bind the cannabinoid receptors. The major pathway leading to NAEs involves an N-acyltransferase (NAT) producing N-acylphosphatidylethanolamines followed by the release of NAEs by NAPE-PLD. sensory process of encoding a ‘potential threat’ signal (heat, cold, trauma, etc.) by the nervous system. a family of lipid mediators generated by the action of COX on AA. characterized by increased sensitivity of neurons to signals and results in the formation of action potentials in response to low-intensity inputs that do not usually trigger them. Sensitization can be peripheral (peripheral nervous system) and/or central (CNS) and occurs during inflammatory or neuropathic pain processes. chemical compounds able to block the activity of an enzyme towards one of its substrates but not the others. In the context of this review, substrate-selective inhibitors of COX-2 inhibits its action on 2-AG and AEA (thus preventing the production of PGH2-G and PGH2-EA, respectively) but not on AA (thus allowing the synthesis of the prostaglandin precursor PGH2).