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This paper focuses on the modes of action and effects of Cannabinoids on the peripheral vs. central nervous system in different tissues relating to certain metabolic disorders. Endocannabinoids exert their specific effects after production in various sites in the brain, like the hypothalamus and mesolimbic reward circuitry. There is a direct relationship between these brain regions and energy metabolism regulation, especially energy expenditure and food intake. According to available data, the beneficial effects of CB1 receptors antagonists as already observed in obesity have a relationship with the central endocannabinoid system.
Furthermore, there is scientific evidence showing that the action of cannabinoids on the white adipose and liver tissues shows that the CB1-mediated events in their effect on metabolic phenotype may come up also in peripheral tissue.
The above, along with results already reported from CB1 antagonist actions in human trials, indicate that there is a reduction in the initial anorectic effect of rimonabant. However, the weight loss effect is long lasting to indicate the importance of the peripheral action of cannabinoids in the regulation of body weight. This indicates that the pharmaceutical approach to obesity can be revolutionized since it will offer a tool short-cutting the central nervous system.
The production of endocannabinoids is on demand, and their synthesis is triggered typically by a rise in intracellular calcium at the postsynaptic sites as a response to synaptic activities especially if the activity is sustained. The major endocannabinoids produced are deactivated rapidly by degrading enzymes and reuptake mechanisms, including monoacylglycerol lipase (MAGL) and fatty acid amide hydrolyses (FAAH). Among the available endocannabinoids, arachidonic acid derivatives like 2-AG and AEA are orthosteric and dominant. They are ligands and also an agonist for both CB1 and CB2 receptors. However, they bind to CB1 receptors with a higher affinity.
In recent times, allosteric endocannabinoids have been discovered, examples of which are lipoxin A4 and pregnenolone, both of which can modulate CB1 receptor signaling to produce a possible therapeutic value. There is still a need for additional pharmacological characterization of allosteric and orthostatic modulators for a clear elucidation of their modes of action and physiological roles. Be that as it may, the actions of endocannabinoids by allosteric modulators or their pharmacological manipulations can provide several alternative opportunities for regulating the endocannabinoid system.
It is established that the hypothalamus is critical to energy balance regulation. The suspicion first came after obesity was recorded in individuals having hypothalamus tumor more than a century ago. It was thought that most of the endocrine functions in the body were regulated by the pituitary gland. Animal studies using brain lesions of hypothalamus structures confirmed that the hypothalamus is critical to energy balance and food intake gross damage to the ventromedial hypothalamic nucleus (VHN) of the mediobasal hypothalamic area is related to insulin resistance, morbid obesity and an increase in food intake.
The activation of the receptors in the cannabinoids peripheral vs. central nervous system have equally been found useful in the treatment of certain diseases as will be discussed below.
The CB1 receptors are involved in several disorders impacting the CNS, some of which are multiple sclerosis and Huntington’s disease. Multiple sclerosis is a neurodegenerative disease manifesting as demyelination with the neuronal and axonal loss. Many clinical trials show a positive effect of CB agonists, including cannabis, on pain, spasms, and spasticity or other signs of multiple sclerosis.
Sativex, a registered drug, is an oromucosal spray containing cannabis extract with a fixed amount of cannabidiol and THC. It leads to the systematic improvement of those with multiple sclerosis. The meta-analysis of many clinical trials shows a drastic reduction in pain and motor dysfunction. Furthermore, reports surfaced about a rise in non-serious side effects. The lack of cost-effectiveness of Sativex is one factor militating against its use as a cure for multiple sclerosis.
Huntington Disease (HD) and experimental models show dysregulation of the endocannabinoid system. There is a reduction in the expression of the CB1 receptor before the neurodegenerative symptoms of HD
Endocannabinoid modulation is therapeutic in several neurodegenerative and neuropsychiatric disorders. The amount of knowledge acquired about the in vivo and in vitro pharmacology of the endocannabinoid receptors has prompted a link between the Cannabinoids peripheral vs. central nervous system, making it one of the most effective treatment methods for several neurodegenerative and metabolic disorders. Be that as it may, further clinical researches are required for concrete evidence of the associated therapeutic potentials in human.0803275a
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