Neuropharmacology of endogenous, synthetic and phytocannabinoids for pain management

The use of cannabis-derived compounds for medical purposes dates from more than two thousand years. Due to its psychotropic effects and cultural aspects related to the plant of origin, its benefits have been disregarded in several western countries. Nevertheless, the number of studies on Cannabis sativa, especially on clinical applications of cannabinoids, increased significantly in the latest years. Amidst the benefits of cannabis-derived compounds is pain relief. Here we review physiological, pharmacological and chemical aspects of pain management in humans with endocannabinoids, synthetic cannabinoids and phytocannabinoids. The analgesia mechanism can be explained not only through interactions with cannabinoid receptors 1 and 2 but also through direct or indirect interaction with serotonin, glycine, gamma-aminobutyric acid, N-methyl-D-aspartate, adrenergic and opioid receptors, as well as transient receptors potential channels. They can also modify the behavior of molecules such as cytokines, calcitonin gene-related protein and substance P, which largely influence pain-related mechanisms. Exogenous cannabinoids are interesting options to consider when it comes to pain management, especially in complex cases associated to poor response to the currently available drug therapy