Targeting the cannabinoid system for pain relief?

Abstract

Marijuana has been used to relieve pain for centuries, but its analgesic mechanism has only been understood during the past two decades. It is mainly mediated by its constituents, cannabinoids, through activating central cannabinoid 1 (CB1) receptors, as well as peripheral CB1 and CB2 receptors. CB2-selective agonists have the benefit of lacking CB1 receptor-mediated CNS side effects. Anandamide and 2-arachidonoylglycerol (2-AG) are two intensively studied endogenous lipid ligands of cannabinoid receptors, termed endocannabinoids, which are synthesized on demand and rapidly degraded. Thus, inhibitors of their degradation enzymes, fatty acid amide hydrolase and monoacylglycerol lipase (MAGL), respectively, may be superior to direct cannabinoid receptor ligands as a promising strategy for pain relief. In addition to the antinociceptive properties of exogenous cannabinoids and endocannabinoids, involving their biosynthesis and degradation processes, we also review recent studies that revealed a novel analgesic mechanism, involving 2-AG in the periaqueductal gray (PAG), a midbrain region for initiating descending pain inhibition. It is initiated by Gq-protein-coupled receptor (GqPCR) activation of the phospholipase C (PLC)-diacylglycerol lipase (DAGL) enzymatic cascade, generating 2-AG that produces inhibition of GABAergic transmission (disinhibition) in the PAG, thereby leading to analgesia. This GqPCR-PLC-DAGL-2-AG retrograde disinhibition mechanism in the PAG can be initiated by activating type 5 metabotropic glutamate receptor (mGluR5), muscarinic acetylcholine (M1/M3), and orexin (OX1) receptors. mGluR5-mediated disinhibition can be initiated by glutamate transporter inhibitors, or indirectly by substance P, neurotensin, cholecystokinin, capsaicin, and AM404, the bioactive metabolite of acetaminophen in the brain. The putative role of 2-AG generated after activating the above neurotransmitter receptors in stress-induced analgesia is also discussed.

Adverse Health Effects of Marijuana Use

“…Studies have shown that cannabinoids acting through central CB1 receptors, and possibly peripheral CB1 and CB2 receptors, 63 play important roles in modeling nociceptive responses in various models of pain. These findings are consistent with reports that marijuana may be effective in ameliorating neuropathic pain, 64,65 even at very low levels of THC (1.29%).…”

Effects of Cannabidiol and a Novel Cannabidiol Analog against Tactile Allodynia in a Murine Model of Cisplatin-Induced Neuropathy: Enhanced Effects of Sub-Analgesic Doses of Morphine

“…CB analgesia in both chronic and acute pain models is mediated through CB1 and CB2 receptors that are differentially expressed in the central and peripheral nervous systems [9,10]. An emerging body of literature supports the notion that endocannabinoid systems may also modulate CIN.…”

Effects of a water extract of Lepidium meyenii root in different models of persistent pain in rats

“…Selective FAAH inhibitors enhance anandamide endogenous levels that cause antinociceptive effect by agonism on the CB 2 receptor [21]. Furthermore, many preclinical studies demonstrated that FAAH inhibitors reduce chronic pain without the development of tolerance after repeated administrations [43].…”

“…Moreover, maca improves the antioxidant cell machinery [19]. Cannabinoid and cholinergic systems [20,21], as well as redox unbalance [22][23][24][25], play a relevant role in persistent pain processes. Maca consumption has been associated with lower serum levels of the proinflammatory and proalgic cytokine IL-6 in populations living in the Peruvian Central Andes [8].…”