Substrates of Human CYP2D6
Shufeng Zhou in 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.
Endogenous Cannabinoid Receptors and Medical Cannabis
Sahar Swidan, Matthew Bennett in Advanced Therapeutics in Pain Medicine, 2020
Considerably more work is needed to fully describe the pharmacology of the orthosteric and allosteric modulators operating on the ECS, but much is already known. The endocannabinoid anandamide is a partial agonist, operating as a modulator more in the periphery, outside the CNS. Anandamide functions as a partial receptor agonist affecting the neurons that regulate pain signaling by controlling the chemical gates through which pain signals access the CNS. By contrast, the endocannabinoid 2-AG is a total agonist, fully activating the cannabinoid receptors. 2-AG has been referred to as the workhorse of the ECS, serving as a point-to-point retrograde messenger to provide fundamental brain and spinal cord functions. Major endocannabinoids are rapidly deactivated by reuptake mechanisms and degrading enzymes.11,12 Cannabinoid receptor activity is also selectively modified by the binding of ligands at allosteric sites on receptors.
Pharmacotherapy of Neurochemical Imbalances
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
The interesting fact observed was that though cannabinoids exist only naturally in plant with no biological connection in humans, many parts of brain, namely cerebral cortex, basal ganglia, cerebellum, and hippocampus express huge numbers of receptors for cannabinoids. This made scientific workers to think of endogenous substances which may be selectively interacting with CB and whose action is facilitated by Delta-9-tetrahydrocannabinol. Thus in 1992, the first endogenous ligand of CB1 receptors later labeled as Anandamide was discovered in porcine brain. The name, Anandamide was derived from the Sanskrit word ‘Ananda’ meaning ‘Bliss.’ With the discovery of anandamide, many other metabolites collectively termed as endocannabinoids, were characterized and discovered to act as useful agonists of CB in the brain, however they were not superior in efficacy than anandamide (Devane et al., 1992). The endocannabinoids are found in the brain or other tissues only in small amounts. Similar to other lipid mediators, they are formed and released locally on call. Anandamide and endocannabinoids are rapidly inactivated by reuptake through transporter and by metabolism through the enzyme fatty acid amide hydrolase. The anandamide is formed from the precursor N-arachidonic phosphatidyl ethanolamine by hydrolysis in presence of an enzyme phosphodiesterase enzyme phospholipase D (Iversen, 2003).
Medicinal cannabis pharmacokinetics and potential methods of delivery
Published in Pharmaceutical Development and Technology, 2022
Lidya Kebede, Seyedehsara Masoomi Dezfooli, Ali Seyfoddin
The entourage effect is not only observed in exogenous cannabinoids but is also demonstrated by endogenous compounds in our body (Fowler 2003). A review that discusses the neuroprotective effects of cannabinoids, suggests that plant-derived compounds are not the only ones that have an entourage effect, but endogenous cannabinoid and related compounds also experience the same phenomena. Anandamide is a well-studied endocannabinoid that is part of the N-acyl ethanolamines group (Fowler 2003). When anandamide was studied on peripheral polymodal nociceptors in normal and inflamed knee joints in rats, its ability to activate vanilloid and cannabinoid receptors was observed (Gauldie et al. 2001). Anandamide’s affinity to those receptors was further increased when used in conjunction with other N-acyl ethanolamines (Fowler 2003). A study that had discovered a new family of bioactive molecules, the arachidonyl amino acids, in the mammalian brain in 2001, had also provided evidence of synergistic interaction between anandamide and arachidonyl-glycine. Arachidonyl-glycine, unlike anandamide, lacks affinity to CB1 and vanilloid VR1 receptors but can suppress tonic pain. When these two molecules are present, they maintain spontaneous pain, allodynia, and hyperalgesia by minimising central sensitisation and leading to reduced pain following an injury (Huang et al. 2001).
Cannabinoid Receptor Type 1 and Its Role as an Analgesic: An Opioid Alternative?
Published in Journal of Dual Diagnosis, 2020
Amber L. Milligan, Thomas A. Szabo-Pardi, Michael D. Burton
One of the most well studied and well-understood pain modulating areas in the central nervous system is the periaqueductal gray in the brainstem. This region is prominent in opioid analgesia and is likely a critical component of the endocannabinoid system as it is densely saturated with CB1 receptors. This area releases endogenous anandamide in response to noxious stimuli, indicating a pivotal region of endocannabinoid action (Walker, Huang, Strangman, Tsou, & Sanudo-Pena, 1999). Electrical stimulation of the PAG has shown analgesic effects after intradermal formalin injection in rats that are associated with increased anandamide release in the PAG. These analgesic effects are attenuated after injection of the CB1R antagonist, S141716, into the PAG, suggesting a critical role of CB1R in this brain region for pain modulation (Walker et al., 1999). Further, injections of WIN 55-212-2 directly into the dorsolateral PAG inhibited nociceptive responses to noxious heat (Martin et al., 1995).
Pharmacological Treatment of Generalised Anxiety Disorder: Current Practice and Future Directions
Published in Expert Review of Neurotherapeutics, 2023
Harry A. Fagan, David S. Baldwin
The endocannabinoid system is a widespread neurotransmitter system, consisting of endogenous ligands (anandamide and 2-AG) and two cannabinoid receptors (CB1 and CB2). Exogenous ligands for cannabinoid receptors are produced by the cannabis plant (Cannabis sativa) and these phytocannabinoids have been widely used throughout human history [136]. Identified phytocannabinoids include Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) [137]. Several synthetic cannabinoids have also been produced. CBD lacks the psychotomimetic effects of Δ9-THC and animal studies indicate a potential anxiolytic effect [138]. However, to date, there are limited clinical studies on the effect of cannabinoids in anxiety disorders [139]. No RCT has considered the effect of cannabinoids in GAD, although one small RCT demonstrated a single dose of CBD (600 mg) reduced anxiety induced by public speaking in patients with SAD [140]. In addition, a crossover RCT demonstrated the efficacy of 7 weeks of treatment with the synthetic cannabinoid nabilone on frequency of nightmares and quality of life in PTSD (albeit with a small sample size of 10 participants) [141].
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