The endocannabinoid system was discovered through research into delta 9 –tetrahydrocannabinol ( THC ), the active ingredient in cannabis.

The endocannabinoid system consists of cannabinoid receptors, endogenous cannabinoids ( endocannabinoids ), and the enzymes that synthesize and degrade endocannabinoids. There are at least two types of cannabinoid receptor, CB1 and CB2. Endogenous agonists for cannabinoid receptors also exist. These endocannabinoids are synthesized on demand in response to elevations of intracellular calcium; the two most notable endocannabinoids are N-arachidonoylethanolamine ( anandamide ) and 2-arachidonoyl glycerol ( 2-AG ).

The endocannabinoid system is found in many regions of the brain including but not limited to: cortex, hippocampus, basal ganglia, cerebellum, striatum, amygdala, and nucleus accumbens; receptor density is particularly high in the cerebellum, cortex, hippocampus, hypothalamus, and basal ganglia. These areas affect memory, motor function, and reward behaviors.

Although CB1 receptors are expressed by certain non-neuronal cells and tissues, for example, the pituitary gland, immune cells, and reproductive tissues, they are found predominantly at central and peripheral nerve terminals where they mediate inhibition of transmitter release. CB2 receptors are expressed mainly on immune cells, where they modulate, both within and outside the central nervous system, cytokine release and immune cell migration. Thus, one common role of CB1 and CB2 receptors appears to be the regulation of ongoing release of chemical messengers, CB1 receptors mainly from neurons and CB2 receptors from immune cells.

As pointed out in a recent review, endocannabinoids are important modulators in the physiological response of the HPA axis during repetitive stress conditions and in pathological conditions, such as anxiety, phobias, depression, and posttraumatic stress disorders. Moreover, the endocannabinoid system has been proposed as playing an important role in protection against neurotoxicity and, possibly, certain forms of epilepsy.

Drugs presumed to increase endocannabinoid tone are therefore currently proposed as a new therapeutic frontier to treat anxiety related disorders and neurodegenerative diseases. The use of drugs acting as antagonists of CB1 receptors should thus be carefully monitored when administered, for instance, to patients with anxiety traits, epilepsy, or neurodegenerative disorders.

There is evidence not only that tissue concentrations of endocannabinoids, cannabinoid receptor density, and/or cannabinoid receptor coupling efficiency increase in a range of different disorders, but also that these increases serve to reduce the severity of signs and symptoms of some of these disorders or even oppose disease progression. Support for the hypothesis that the endocannabinoid system has such an autoprotective role has so far come mainly from experiments concerned with pain, multiple sclerosis, cancer, intestinal, mental and cardiovascular disorders, excitotoxicity, traumatic head injury, and Parkinson’s disease.

The endocannabinoid system is believed to play a role in the following:

• Pain - CB1 receptors are located on pain pathways in the brain and spinal cord and on the central and peripheral terminals of primary afferent neurons that mediate both neuropathic and non-neuropathic pain. Animal studies indicate that the endogenous cannabinoid anandamide and cannabinoid ligands are very effective against chronic pain of both neuropathic and inflammatory origin. Cannabinoid agonists may also release endogenous opioids, and a functional interplay between the endocannabinoid and opioid systems in modulating analgesic responses has been suggested by numerous studies.

• Multiple sclerosis - There is evidence from clinical trials with multiple sclerosis patients that cannabinoids can reduce the spasms, spasticity, or tremor of multiple sclerosis. Furthermore, results from studies using mouse models of multiple sclerosis suggest that cannabinoid CB1 or CB2 receptor activation by exogenously administered or endogenously released agonists may oppose the progression of multiple sclerosis by slowing the neurodegenerative process, reducing inflammation, and promoting remyelination.

• Cancer - Numerous studies have suggested that cannabinoids might directly inhibit cancer growth. The proposed mechanisms are complex and may involve induction of apoptosis in tumor cells, anti-proliferative action, and an anti-metastatic effect through inhibition of angiogenesis and tumor cell migration.

• Intestinal disorders - There is evidence that: first, that certain disorders characterized by inflammation of the gastrointestinal tract or by diarrhea may be associated with an increase in intestinal endocannabinoid levels and/or in the expression of CB1 receptors by mesenteric neurons; second, that the resultant hyperactivity of the endocannabinoid system ameliorates at least some of the symptoms of these diseases; and third, that this amelioration can be mimicked by CB1 receptor agonists or enhanced by inhibitors of endocannabinoid metabolism.

• Mental disorders - Studies have shown that levels of anandamide are markedly higher in the cerebrospinal fluid of anti-psychotic-naïve first-episode paranoid schizophrenics and of schizophrenics taking atypical anti-psychotics than in the cerebrospinal fluid of healthy controls. CSF anandamide levels are negatively correlated with psychotic symptoms in schizophrenic patients. It is hypothesized that anandamide has a protective role in schizophrenia.

• Excitotoxicity - It has been found that kainic acid elevates anandamide in the hippocampus and that this excitotoxin induces more severe seizures when the CB1 receptor is genetically deleted or pharmacologically blocked.

• Cardiovascular disorders - CB1 receptors are much more important than CB2 receptors in cardiovascular regulation. CB1 receptors have been detected in the human, rat, and mouse myocardium where they mediate negative inotropy and also in vascular tissues, where their activation leads to vasodilation. Both of these effects appear to be involved in the hypotensive effect of anandamide. Sympathetic nerve terminals contain presynaptic CB1 receptors, stimulation of which inhibits norepinephrine release, which contributes to the bradycardic effects of anandamide in vivo.

• Eye disorders - Endocannabinoids and cannabinoid receptors, in particular CB1, play an important role in the regulation of intraocular pressure. Endocannabinoids as well as functional CB1 receptors are present in the retina. Cannabinoids exert neuroprotective effects against retinal neurotoxicity.

Source: FDA, 2007

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