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Endocannabinoids & Phytocannabinoids in Pain Management *
Published in Betty Wedman-St Louis, Cannabis as Medicine, 2019
Endocannabinoids produced within the body including anandamide (arachidonyl ethanolamide) and 2-arachidonylglycerol (2-AG) are able to activate receptors in the endocannabinoid system. Two important receptors in this system that are involved in pain management are CB1 and CB2.10 In the central nervous system, CB2 receptor mRNA is not present in the neuronal tissue of human or rat brains.11 However, it is found in brain cells known as microglia when they are activated.11 Microglia can become activated in states of inflammation and activated microglia themselves can produce pro-inflammatory molecules. The presence of CB2 in activated microglia indicates it may be involved in blocking the effect of painful stimuli in inflammatory processes of the nervous system.11 Activation of CB2 receptors blocks the pain response to thermal and mechanical stimuli,12,13 thermal and tactile hypersensitivity produced by peripheral inflammation,13–15 and neuropathic pain.16 The effects of CB2 receptors on neuropathic pain and inflammation are particularly noteworthy as those conditions are often resistant to treatment, as noted earlier.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Anandamide is the endogenous ligand to the cannabinoid receptor CB1, which is also activated by the main psychoactive component in marijuana. Snider et al. (2008) have revealed that recombinant CYP2D6 converts anandamide to 20-hydroxyeicosatetraenoic acid ethanolamide and 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides with low micromolar Km values. CYP2D6 together with 3A4 and 4F2 further metabolize the epoxides of anandamide to form novel dioxygenated derivatives. The 5,6-epoxide of anandamide, 5,6-epoxyeicosatrienoic acid ethanolamide, is a potent and selective CB2 agonist (Snider et al. 2009). Human brain microsomal and mitochondrial preparations metabolize anandamide to hydroxylated and epoxygenated metabolites, respectively (Snider et al. 2008). These results suggest that anandamide is a physiological substrate for brain mitochondrial CYP2D6, implicating this highly polymorphic enzyme as a potential component of the endocannabinoid system in the brain.
Pea
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
The topic of peroxisome proliferator-activated receptor (PPAR) ligands typically involves a discussion of the lipid-lowering effects of fibrates and the blood sugar-lowering effects of thiazolidinediones. However, more recent research has investigated the role of the endogenous PPAR-α ligand, palmitoylethanolamide (PEA) on inflammation, pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders.1 Palmitoylethanolamide is a naturally occurring fatty acid belonging to the N-acylethanolamine (NAE) class of signaling molecules and can be isolated from egg yolks, peanut meal, and lecithin. It is rapidly metabolized in the human body via fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA) to inactive metabolites palmitic acid and ethanolamide.2,3 Initial pharmacokinetic research by Lambert et al.2 assumed a ligand-binding relationship between PEA and the endogenous cannabinoid 2 (CB2) receptor. However, these initial claims proved to be incorrect and were explained as the entourage effect, where PEA competes with the endocannabinoid anandamide (AEA) for FAAH, resulting in higher concentrations of AEA.4 Although it does have a structural relationship to AEA and other endocannabinoids, PEA was found to have pharmacologic activity at PPAR-α, PPAR-γ, PPAR-δ, G protein-coupled receptor (GPR) 55, GPR119, transient receptor potential channel type (TRP) V1, ATP-sensitive potassium channels, and calcium-activated potassium channels. Additionally, PEA appears to inhibit ceramidases, and potassium channels Kv4.3 and Kv1.5, as well as interacting with NF-κB, cyclooxygenase (COX), TNFα, interleukin (IL)-4, IL-6, IL-8, nitric oxide (NO), and substance P mast cell activation. This variety of interactions has afforded PEA the title of being “promiscuous.”4,5
A review on neuropharmacological role of erucic acid: an omega-9 fatty acid from edible oils
Published in Nutritional Neuroscience, 2022
J. B. Senthil Kumar, Bhawna Sharma
In a separate study, erucamide (5, 10, 20 mg/kg, p.o.), exhibited antidepressant, anxiolytic-like behaviour mice using fluoxetine (20 mg/kg, p.o.) as a standard drug [119]. In the forced swim test and tail suspension test, immobility was measured as an indicator of antidepressant-like behaviour. For exploratory behaviour and anxiety-like behaviours open field test and elevated plus-maze test were recorded in mice. Other parameters such as serum adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) levels were recorded and the total anti-oxidative capacity (T-AOC) was detected by UV spectrophotometry. Biochemical tests revealed that, ACTH and CORT serum levels in mice were significantly decreased, although T-AOC levels did not significantly change. Based on these finding, it was suggested that erucamide may alleviate depression and anxiety-like behaviours in mice, and these effects may be related to the regulation of the hypothalamus-pituitary-adrenal axis (HPA). Moreover we believe that these effect were may be due to the structural resemblance of erucamide with oleoylethanolamide, a natural ethanolamide analogue of anandamide (Figure 7).
Omega‐3 Polyunsaturated Fatty Acids and Lung Cancer: nutrition or Pharmacology?
Published in Nutrition and Cancer, 2021
Owen M. Vega, Shaheen Abkenari, Zhen Tong, Austin Tedman, Sara Huerta-Yepez
More recently, a research team, Roy, J et al. investigated the role of docosahexaenoyl ethanolamide (DHEA), a compound derived from the ω-3 PUFA DHA. A new class of anti-inflammatory DHEA-epoxide derivatives, EDP-EA, are defined to have antitumorigenic properties. In a mouse model using 6-8-week-old female BALB/c mice injected with K7M2, osteosarcoma cells, their results demonstrated around 80% increase of these metabolites in metastasized lungs in contrast to normal lungs. The authors investigated whether the presence of these metabolites was promoting tumor growth or exhibiting antitumorigenic properties and found that the increase of these EDP-EAs are anti-inflammatory, antiangiogenic and antimetastatic (99). The researchers conclude that ω-3 PUFA metabolites therefore reduce the migratory potential of cancer cells, and that EDP-EAs induce apoptosis.
Cannabis for cancer – illusion or the tip of an iceberg: a review of the evidence for the use of Cannabis and synthetic cannabinoids in oncology
Published in Expert Opinion on Investigational Drugs, 2019
Cannabinoids are classified according to their source of production: synthetic cannabinoids are manufactured for use in research and development of therapeutic agents; phytocannabinoids occur naturally in the Cannabis plant; and endocannabinoids (eCBs) such as N-arachidonoyl ethanolamide (AEA, anandamide) and 2-arachidonoyl glycerol (2-AG) are produced endogenously by humans and other mammals. Cannabinoid types are delineated in Figure 1.