ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several 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.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

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Intrathecal cannabinoid-1 receptor agonist prevents referred hyperalgesia in acute acrolein-induced cystitis in rats.

“We investigated the capacity of intrathecal arachidonyl-2′-chloroethylamide (ACEA), a cannabinoid-1 receptor (CB1R) agonist, to inhibit referred hyperalgesia and increased bladder contractility resulting from acute acrolein-induced cystitis in rats…

These findings suggest that pain arising from cystitis may be inhibited by activation of spinal CB1R but the acute local response of the bladder appeared to be unaffected by stimulation of spinal CB1R.”

http://www.ncbi.nlm.nih.gov/pubmed/26069885

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The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain.

“The therapeutic effects of the cannabinoid anandamide and the putative CB2 agonist palmitoylethanolamide were tested in a model of persistent visceral pain (turpentine inflammation of the urinary bladder)…

The results confirm the analgesic potential of endogenous ligands at cannabinoid receptor sites.

The anti-nociceptive effect of the putative CB2 receptor agonist, palmitoylethanolamide, is particularly interesting since it is believed to be a peripherally mediated effect.

This observation might be exploited to separate central psychotropic effects from peripheral analgesic actions of the cannabinoids, under inflammatory conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/9696473

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Cannabinoid receptor 2 is increased in acutely and chronically inflamed bladder of rats.

“Cannabinoid receptors are expressed in the urinary bladder and may affect bladder function… CB2 receptors may be a viable target for pharmacological treatment of bladder inflammation and associated pain…

In this study, we have shown that CB1 and CB2 are present in the bladder and its innervation, and that expression of CB2 is increased in the bladders of rats with acute and chronic cystitis. Bladder inflammation and pain is the summation of a number of biological events, including participation of the endocannabinoid system.

The endocannabinoid system could play an important role in modulation of severity of bladder inflammation and pain, and it may be possible to take advantage of the cannabinoid system in the bladder to decrease inflammation and resultant pain.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2592089/

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Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis.

  Figure 4.

“The role of anandamide in the development of inflammatory hyperalgesia and visceral hyperreflexia was studied in the rat urinary bladder…

These results suggest that anandamide, through activating TRPV1, contributes to the development of hyperreflexia and hyperalgesia during cystitis.”

http://www.jneurosci.org/content/24/50/11253.long

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Increased cannabinoid receptor 1-immunoreactive nerve fibers in overactive and painful bladder disorders and their correlation with symptoms.

“To study the expression of cannabinoid receptor 1 (CB1) in human urinary bladder hypersensitivity and overactivity disorders, and correlate changes with symptoms. Cannabinoid receptor agonists have been shown to modulate urinary bladder contractility and reduce pain after bladder inflammation; their clinical efficacy on lower urinary tract symptoms was demonstrated in the Cannabinoids in Multiple Sclerosis study…

CONCLUSIONS:

The results of this study suggest that increased nerve fibers, which express CB1, may be related to bladder pain in PBS (painful bladder syndrome) and urgency in IDO (idiopathic detrusor overactivity).

Our findings support clinical trials of CB1 agonists in bladder disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/20346490

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Differential expression of functional cannabinoid receptors in human bladder detrusor and urothelium.

“Although cannabinoid receptor expression has been demonstrated in human brain and other peripheral neuronal tissues, definitive expression of these receptors in the human bladder has not been reported. Consequently we investigated the expression of functional cannabinoid 1 and 2 receptors in human bladder detrusor and urothelium…

CONCLUSIONS:

Together these findings suggest a physiological role of cannabinoid 1 and 2 receptors in the human bladder.

Moreover, these results confirm the presence of functional cannabinoid 1 and 2 receptors in the human bladder, which can serve as a target for drugs acting on symptoms of interstitial cystitis/painful bladder syndrome.”

http://www.ncbi.nlm.nih.gov/pubmed/19237176

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Functional and immunohistochemical characterization of CB1 and CB2 receptors in rat bladder.

“To determined the localization of CB(1) and CB(2) receptors in rat bladder and investigate the effect of a mixed CB(1)/CB(2) receptor agonist, ajulemic acid (AJA), on chemically evoked release of the sensory neuropeptide calcitonin gene-related peptide (CGRP)…

CONCLUSIONS:

CB(1) and CB(2) receptors are localized in the urothelium of rat bladder, and application of AJA inhibits the evoked release of CGRP by acting on CB(1) and CB(2) receptors.

These findings identify a potential new pathway for study in the evaluation and treatment of painful bladder syndrome/interstitial cystitis.”

http://www.ncbi.nlm.nih.gov/pubmed/18468662

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Treatment with a Cannabinoid Receptor 2 Agonist Decreases Severity of Established Cystitis.

“We investigated whether treatment with the selective cannabinoid receptor 2 agonist… would ameliorate the severity of experimental cystitis…

Treatment with a selective cannabinoid receptor 2 agonist decreased severity of established acrolein induced cystitis and inhibited bladder inflammation associated increased referred mechanical sensitivity and increased bladder urinary frequency.

Our data indicate that cannabinoid receptor 2 is a potential therapeutic target for treatment of painful inflammatory bladder diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/24184363

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