The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

Abstract

Cannabinoids are a group of chemical compounds that produce their effects via activating cannabinoid receptors; they include the phytocannabinoids (herbal cannabinoids/natural cannabinoids found in the cannabis plant), synthetic cannabinoids, and endogenous cannabinoids (endocannabinoids) (1, 2). Cannabis, also known as marijuana, has been used as both a recreational and medicinal drug for centuries. Pain management is the most important among the medicinal purposes, and has been drawing intense attention following the discovery of cannabinoid receptors and their endogenous ligands, endocannabinoids (3-5). ∆ 9 -tetrahydrocannabinol (THC) and cannabidiol, the critical components of the cannabis plant, and the synthetic cannabinoids and their analogues have been shown to exert strong analgesic action both in preclinical and clinical studies (6)(7)(8)(9). In this review, after a brief introduction to cannabinoid receptors, phytocannabinoids and synthetic cannabinoids, I provide an overview of what is currently known about the synthesis, release, degradation and biological actions of endocannabinoids, regarding their role in pain modulation, and describe the recent evidence of the promising results of augmentation of endogenous cannabinoid tonus for the treatment of pain. CANNABINOID RECEPTORS AND THE SITE OF ACTION OF CANNABINOIDSTo date, two subtypes of cannabinoid receptors, termed cannabinoid-1 (CB 1 ) and cannabinoid-2 (CB 2 ) receptors, have been cloned (10, 11). CB 1 receptors are most abundantly expressed in the central nervous system (CNS), most densely in motor and limbic regions, and in areas that are involved in pain transmission and modulation, such as periaqueductal grey (PAG), rostral ventromedial medulla (RVM), spinal cord dorsal horn, and in the periphery. CB 1 receptors are generally located pre-synaptically on axons and terminals of neurons and mediate the inhibition of neurotransmitter release by the inhibition of adenylate cyclase, blockade of voltage-dependent calcium channels, and/or by the activation of potassium channels and mitogen-activated protein kinase. CB 2 receptors, on the other hand, are found mainly, but not exclusively, outside the CNS, predominantly in peripheral tissues with immune functions, and most densely in the spleen. Similar to CB 1 receptors, CB 2 receptors are also G-protein coupled, inhibits adenylate cyclase and produce cellular inhibition, but neither blockade of calcium channels Although cannabis has been used for pain management for millennia, very few approved cannabinoids are indicated for the treatment of pain and other medical symptoms. Cannabinoid therapy re-gained attention only after the discovery of endocannabinoids and fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the enzymes playing a role in endocannabinoid metabolism. Nowadays, research has focused on the inhibition of these degradative enzymes and the elevation of endocannabinoid tonus locally; special emphasis is given on multi-target analgesia compounds, where one of the targe...

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