The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain

Abstract

A great need exists for the development of new medications to treat pain resulting from various disease states and types of injury. Given that the endogenous cannabinoid (that is, endocannabinoid) system modulates neuronal and immune cell function, both of which play key roles in pain, therapeutics targeting this system hold promise as novel analgesics. Potential therapeutic targets include the cannabinoid receptors, type 1 and 2, as well as biosynthetic and catabolic enzymes of the endocannabinoids N-arachidonoylethanolamine and 2-arachidonoylglycerol. Notably, cannabinoid receptor agonists as well as inhibitors of endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase produce reliable antinociceptive effects, and offer opioid-sparing antinociceptive effects in myriad preclinical inflammatory and neuropathic pain models. Emerging clinical studies show that 'medicinal' cannabis or cannabinoid-based medications relieve pain in human diseases such as cancer, multiple sclerosis, and fibromyalgia. However, clinical data have yet to demonstrate the analgesic efficacy of inhibitors of endocannabinoid-regulating enzymes. Likewise, the question of whether pharmacotherapies aimed at the endocannabinoid system promote opioid-sparing effects in the treatment of pain reflects an important area of research. Here we examine the preclinical and clinical evidence of various endocannabinoid system targets as potential therapeutic strategies for inflammatory and neuropathic pain conditions.

Figure 1

Endocannabinoid system localization by CNS cell type. Drugs acting upon cannabinoid receptors and the endocannabinoid-regulating enzymes are determined not only by drug class, efficacy, affinity, and potency, but also by cellular compartmentalization of the drug target. 2-AG, 2-arachidonyl glycerol; ABHD6, α/β-hydrolase domain-6; ABHD12, α/β-hydrolase domain-12; AEA, anandamide; CB₁, cannabinoid receptor 1; CB₂, cannabinoid receptor 2; DAGL-α, diacylglycerol lipase-α; DAGL-β, diacylglycerol lipase-β; FABP, fatty acid binding protein; FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; NAPE, N-arachidonoyl phosphatidylethanolamine; PPAR-α, peroxisome proliferator-activated receptor alpha; TRPV1, transient receptor potential cation channel subfamily V member 1. Question marks refer to conflicting evidence to support the targets cellular localization.

Figure 2

Enzymatic regulation of endocannabinoids and primary targets. Endogenous cannabinoids are enzymatically regulated, produced, and released on demand. Anandamide and 2-AG bind and activate CB₁ and CB₂ receptors. Anandamide also binds and activates transient receptor potential cation channel subfamily V member 1 (TRPV1). Diacylglycerol lipase (DAGL) alpha and beta synthesize 2-arachidonoylglycerol. N-acyl phosphatidylethanolamine-selective phospholipase D (NAPE-PLD*) is one of several enzymes proposed to synthesize anandamide. Monoacylglycerol lipase (MAGL), alpha/beta-hydrolase domain containing (ABHD) 6 and 12 hydrolyze 2-AG to create arachidonic acid. Several enzymes, including cyclooxygenase (COX) 1 and 2 and lipoxygenases (LOXs) convert arachidonic acid into bioactive lipids. COX2 also converts anandamide to prostaglandin-ethanolamides, and 2-AG to prostaglandin glycerol esters. Thick blue or red lines with arrows represent major degradative pathways for 2-AG and anandamide, respectively. Dashed lines with arrows represent other degradative pathways. Reverse arrows (Y) represent activation of receptor targets of each endocannabinoid.