ABSTRACT
BACKGROUND AND OBJECTIVES:
The change of paradigm in relation to the medical use of cannabis and its components in the treatment of pain is undeniable nowadays. Understanding the functioning of the endocannabinoid system and its interaction with drugs already available on the market is necessary for professionals who care for patients with chronic pain. The aim of this study was to show the mechanisms by which cannabinoids act, not only on CB1 and CB2 receptors, but also on various other receptors, modulating chronic pain, and encourage health professionals to recognize the need to expand the knowledge about its functioning and synergism with several medications so that the safe use of cannabis occurs in the treatment of multiple diseases, especially chronic pain.
CONTENTS:
The action of cannabinoids on the endocannabinoid system has the ability to neuro and immunomodulate pain transmission in a multifactorial and extremely complex way, acting simultaneously on multiple targets, in the peripheral, spinal and supraspinal nervous system. The analgesia mechanisms determined by cannabinoids include the inhibition of the release of neurotransmitters and neuropeptides in presynaptic nerve terminals, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pathway and reduction of neural inflammation. There is also the possibility that the interaction of cannabinoids with opioid and serotonergic receptors has an amplifying effect on the analgesic effect of drugs belonging to the opioid class.
CONCLUSION:
The endocannabinoid system plays a key role in pain control and its pathophysiology. It is expected that this system will continue to be studied for a better understanding of its signaling pathways and metabolism, and also that more clinical trials of greater size and duration will be carried out to understand to what extent this approach can be beneficial in the treatment of chronic pain.
Keywords:
Cannabis sativa
; Chronic pain; Endocannabinoids
HIGHLIGHTS
The endocannabinoid system is a defense against excitotoxicity in situations of neuronal hyperactivity and can mitigate the chronification of pain.
The system works in an antidromic way. In chronic pain, exogenous doses can restore more effective conditions of functioning and modulation.
Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) directly activate glycine receptors, contributing to cannabinoid-induced analgesia in inflammatory and neuropathic pain, while 2-arachidonoylglycerol (2-AG) and CBD are positive allosteric modulators, mainly in the α2 subunits of the GABAA receptor. The 2-AG signaling cascades in microglial cells mediate the effects of persistent pain.
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(a) The variation of postsynaptic membrane excitability triggers the synthesis of 2-AG. (b) 2-AG travels retrograde to stimulate CB1 receptors on presynaptic terminals, which in turn activate K+ channels and inversely inhibit Ca++ channels, thus inhibiting excitatory neurotransmitter release. 2-AG is metabolized in the presynaptic neuronwith MAGL into arachidonic acid and glycerol. The concept shown in the figure is defended by a study3 and does not include glial participation (especially astroglia). 2-AG, 2-arachidonoylglycerol; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; DAG, diacylglycerol; DAGL-α and DAGL-β, diacylglycerol lipase-α or diacylglycerol lipase-β; MAGL, monoacylglycerol lipase; PA, phosphatidic acid; PLCβ, phospholipase Cβ; PIP2, sn-2-arachidonoyl-phosphatidylinositol-4,5-bisphosphate; MAPK, mitogenactivated protein kinase; GPCR, G protein-coupled receptors.
