Pharmacol Res. Aug;60(2) doi: /rodance.info Epub Apr The endocannabinoid system: role in glucose and energy. PURPOSE OF REVIEW: Growing evidence suggests an important role in metabolic control of the endocannabinoid system, which is composed of cannabinoid. [The role of the endocannabinoid system in the regulation of endocrine function in the liver and adipose tissue as well as glucose metabolism in muscle cells.
In Metabolism The System’s Endocannabinoid Role
It is composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are found throughout the body in the brain, organs, connective tissues, glands, and immune cells.
In each tissue, the cannabinoid system performs different tasks, but the goal is always the same: In fact, almost every physiological process is affected by the endocannabinoid system on some level. This means it can be targeted to treat many diseases. Raphael Mechoulam, the godfather of cannabis research, first identified and isolated tetrahydrocannabinol THC for the first time.
THC is historically known for its psychoactive properties. In addition, Mechoulam also successfully isolated cannabidiol CBD , a non-psychotropic cannabinoid and generally associated with antioxidant and neuroprotectant properties.
These cannabinoids are referred to as "phytocannabinoids" because they are naturally occuring in plants. Being able to isolate these phytocannabinoids for the first time was a critical stepping stone in discovering the endocannabinoid system. This was the first time the endocannabinoid system was defined. Endocannabinoids are cannabinoids that are naturally produced in the body by the brain.
These endocannabinoids bind to cannabinoid receptors on target cells throughout the body, triggering a cellular response which is amplified or diminished as metabolic enzymes destroy or make more endocannabinoids. This activity produces diverse effects that range from anti-inflammatory responses to euphoria.
These discoveries triggered an explosion of research exploring the endocannabinoid system. The system has been implicated in multiple physiological functions and we now have valuable knowledge about the pharmacology, biochemistry, and clinical effects of endocannabinoids.
It has been established that endocannabinoids have a role in the pathology of many disorders and it is believed that they also serve a "protective role" in many medical conditions.
Diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson's disease, Huntington's disease, Alzheimer's disease and Tourette's syndrome could possibly be treated by drugs modulating endocannabinoid system.
There are at least two types of cannabinoid receptors. Many of the effects of cannabinoids and endocannabinoids are mediated by two G protein-coupled receptors GPCRs , CB1 and CB2, although there is new evidence that additional receptors may be involved.
CB1 receptors are primarily found in several brain regions and the central nervous system. A decrease of anandamide was found along the axis that contributed to basal hypersecretion of corticosterone ; in contrast, an increase of 2-AG was found in the amygdala after repeated stress, which was negatively correlated to magnitude of the corticosterone response.
All effects were abolished by the CB 1 antagonist AM , supporting the conclusion that these effects were cannabinoid-receptor dependent. These contrasting effects reveal the importance of the endocannabinoid system in regulating anxiety -dependent behavior.
Results suggest that glutamatergic cannabinoid receptors are not only responsible for mediating aggression, but produce an anxiolytic-like function by inhibiting excessive arousal: In contrast, GABAergic neurons appear to control an anxiogenic-like function by limiting inhibitory transmitter release. Taken together, these two sets of neurons appear to help regulate the organism's overall sense of arousal during novel situations.
Evidence suggests that endocannabinoids may function as both neuromodulators and immunomodulators in the immune system. Here, they seem to serve an autoprotective role to ameliorate muscle spasms, inflammation, and other symptoms of multiple sclerosis and skeletal muscle spasms. These receptors have also been implicated in the proper migration of B cells into the marginal zone MZ and the regulation of healthy IgM levels.
Historical records from ancient China and Greece suggest that preparations of Cannabis indica were commonly prescribed to ameliorate multiple sclerosis-like symptoms such as tremors and muscle pain. Modern research has confirmed these effects in a study on diseased mice, wherein both endogenous and exogenous agonists showed ameliorating effects on tremor and spasticity.
It remains to be seen whether pharmaceutical preparations such as dronabinol have the same effects in humans. Taken together, these studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function reviewed in Pertwee, ; Mollna-Holgado et al.
The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamide secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity.
In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall. For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low. Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the autonomic nervous system. Research found that the CB 1 receptor is expressed presynaptically by motor neurons that innervate visceral organs. Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from sympathetic nervous system nerves.
Other studies have found similar effects in endocannabinoid regulation of intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems. At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in the dorsal horn, possibly by modulating descending noradrenaline input from the brainstem. The endocannabinoid most researched in pain is palmitoylethanolamide. Palmitoylethanolamide is a fatty amine related to anandamide, but saturated and although initially it was thought that palmitoylethanolamide would bind to the CB1 and the CB2 receptor, later it was found that the most important receptors are the PPAR-alpha receptor , the TRPV receptor and the GPR55 receptor.
Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications  and found to be safe and effective. Basically these data are proof of concept for endocannabinoids and related fatty amines to be therapeutically useful analgesics; palmitoylethanolamide is available under the brand names Normast and PeaPure as nutraceuticals. Endocannabinoids are involved in placebo induced analgesia responses. Increased endocannabinoid signaling within the central nervous system promotes sleep-inducing effects.
Intercerebroventricular administration of anandamide in rats has been shown to decrease wakefulness and increase slow-wave sleep and REM sleep. Anandamide is an endogenous cannabinoid neurotransmitter that binds to cannabinoid receptors. In mice it was demonstrated that certain features of a runner's high depend on cannabinoid receptors. Pharmacological or genetic disruption of cannabinoid signaling via cannabinoid receptors prevents the analgesic and anxiety-reducing effects of running.
Neuroscientists often utilize transgenic CB 1 knockout mice to discern novel roles for the endocannabinoid system. While CB 1 knockout mice are healthy and live into adulthood, there are significant differences between CB 1 knockout and wild-type mice. When subjected to a high-fat diet, CB 1 knockout mice tend to be about sixty percent leaner and slightly less hungry than wildtype. The endocannabinoid system is by molecular phylogenetic distribution of apparently ancient lipids in the plant kingdom, indicative of biosynthetic plasticity and potential physiological roles of endocannabinoid-like lipids in plants,  and detection of arachidonic acid AA indicates chemotaxonomic connections between monophyletic groups with common ancestor dates to around million years ago silurian ; devonian.
From Wikipedia, the free encyclopedia. This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Further information on receptor localization: This section provides insufficient context for those unfamiliar with the subject.
Please help improve the article with a good introductory style. January Learn how and when to remove this template message. The Journal of Sexual Medicine. European Journal of Pharmacology. The traditional view that PA engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system ECS , composed of endogenous lipids, their target receptors, and metabolic enzymes.
Indeed, direct and indirect evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. To our knowledge, the first experimental study aimed at investigating the influence of PA on ECS in humans was carried out in by Sparling and coworkers , who showed increased plasma AEA content after 45 min of moderate intensity exercise on a treadmill or cycle ergometer.
Since then, other human studies have shown increased blood concentrations of AEA A dependence of the increase of AEA concentration on exercise intensity has also been documented. Several experimental data support the hypothesis that ECS might, at least in part, explain PA effects on brain functions, because: Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's high', which may function to encourage habitual aerobic exercise.
Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes. How mobility and movement are at the center of human evolution. Issues, News, and Reviews Cell Death and Differentiation. British Journal of Pharmacology. Int J Obes Lond. Indeed, a fold increase in the potency of hypocretin-1 to activate the ERK signaling was observed when CB1 and HcrtR1 were co-expressed These data provide unambiguous identification of CB1-HcrtR1 heteromerization, which has a substantial functional impact.
The existence of a cross-talk between the hypocretinergic and endocannabinoid systems is strongly supported by their partially overlapping anatomical distribution and common role in several physiological and pathological processes. However, little is known about the mechanisms underlying this interaction. CB1 is present in neurons of the enteric nervous system and in sensory terminals of vagal and spinal neurons in the gastrointestinal tract Massa et al. Activation of CB1 is shown to modulate nutrient processing, such as gastric secretion, gastric emptying, and intestinal motility.
CB1 is shown to co-localize with the food intake inhibiting neuropeptide, corticotrophin-releasing hormone, in the paraventricular nucleus of the hypothalamus, and with the two orexigenic peptides, melanin-concentrating hormone in the lateral hypothalamus and with pre-pro-orexin in the ventromedial hypothalamus Inui, ; Horvath, The ECS works through many anorexigenic and orexigenic pathways where ghrelin, leptin, adiponectin, endogenous opioids, and corticotropin-releasing hormones are involved Viveros et al.
OX1—CB1 dimerization was suggested to strongly potentiate orexin receptor signaling, but a likely explanation for the signal potentiation is, instead, offered by the ability of OX1 receptor signaling to produce 2-arachidonoyl glycerol, a CB1 receptor ligand, and a subsequent co-signaling of the receptors Haj-Dahmane and Shen, ; Turunen et al. However, this does not preclude dimerization. Orexin receptor subtypes readily formed homo- and hetero di mers, as suggested by significant BRET signals.
CB1 receptors formed homodimers, and they also heterodimerized with both orexin receptors. However, it is unclear whether this affects their signaling. As orexin receptors efficiently signal via endocannabinoid production to CB1 receptors, dimerization could be an effective way of forming signal complexes with optimal cannabinoid concentrations available for cannabinoid receptors.
Activation of central CB1R The Open Pain Journal. From Bench to Bedside 1st ed. A popular belief has been that endogenous endorphins mediate these beneficial effects.
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The endocannabinoid system and energy metabolism. actions have been attributed to endocannabinoids, and their involvement in several pathophysiological. The endocannabinoid system (ECS) has emerged as one of the most relevant regulators of energy balance. The ECS acts through two. Interestingly, the endocannabinoid system was recently shown to control several metabolic functions by acting on peripheral tissues such as.