Category Archives: Pain

Therapeutic potential of endocannabinoid-hydrolysing enzyme inhibitors.

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Abstract

“The specific protein target of delta9-tetrahydrocannabinol (delta9-THC), the main active ingredient of Cannabis sativa L., was characterized from rat brain nearly 20 years ago, and several endogenous compounds and proteins comprising the endocannabinoid (eCB) system have since been discovered. It has become evident that the eCB system consists of at least two cannabinoid receptors (i.e. the CB1 and CB2 receptors), in addition to their endogenous ligands (the eCBs) and several enzymes involved in the biosynthesis and catabolism of the eCBs. The two well-established eCBs, N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), are produced by neurons on demand, act near their sites of synthesis and are effectively metabolized by fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL), respectively. Inhibitors specifically targeting these enzymes could offer novel therapeutic approaches (e.g. for the treatment of pain and movement disorders). This MiniReview summarizes the literature concerning the potential therapeutic potential of FAAH and MGL inhibitors.”

http://www.ncbi.nlm.nih.gov/pubmed/17910610

A molecular basis of the therapeutic and psychoactive properties of cannabis (delta9-tetrahydrocannabinol).

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Abstract

“All of the therapeutic properties of marihuana (analgesic, antiemetic, appetite stimulant, antiglaucoma) have been duplicated by the tetrahydrocannabinol (THC) molecule or its synthetic derivatives. Today, the molecular mechanisms of action of these compounds have led to a general understanding of the pharmacological effects of marihuana and of its therapeutic properties. These mechanisms involve the specific binding of THC to the 7-transmembrane (7TM) domain G protein-linked receptor, a molecular switch which regulates signal transduction in the cell membrane. The natural ligand of the 7TM receptor is an eicosanoid, arachidonylethanolamide (AEA), generated in the membrane and derived from arachidonic acid. THC acts as a substitute ligand to the 7TM receptor site of AEA. THC would deregulate the physiological function of the 7TM receptor and of its ligand AEA. As a result, the therapeutic effects of the drug may not be separated from its adverse psychoactive and cardiovascular effects. The binding of THC to the 7TM receptor site of AEA induces allosteric changes in the receptor sites of neurotransmitter and opiates resulting in variable interactions and pharmacological responses. The pharmacokinetics of THC with its prolonged storage in fat and its slow release result in variable and delayed pharmacological response, which precludes precise dosing to achieve timely therapeutic effects. The experimental use of THC and of its synthetic analogues, agonists, and antagonists has provided novel information in the nature of molecular signaling in the cell membrane. As a result, the relationships between allosteric receptor responsiveness, molecular configuration of proteins, and physiological regulation of cellular and organ function may be further investigated.”

http://www.ncbi.nlm.nih.gov/pubmed/12188105

Cannabis and endocannabinoid modulators: Therapeutic promises and challenges.

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   “The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control.”

“Marijuana and cannabinoids as medicine”

“Although references to potential medicinal properties of cannabis date to ancient times, and despite cannabis being included as a medication in Western pharmacopeias from the nineteenth through the early twentieth centuries, there is still no body of reliable information on possible indications or efficacy. In part, slow progress can be attributed to difficulties in identifying the active ingredients in cannabis; THC was not actually characterized and identified as the main psychoactive substance until 1965. The chemical properties of the cannabinoids, for example their virtual insolubility in water, and the fact that they consist of oily liquids at room temperature has posed further challenges in formulation and administration. Increased governmental concerns about the abuse potential of marijuana and hashish also created a regulatory climate in many Western countries that emphasized the negative properties of these substances and absence of any documented medicinal properties, thus discouraging research into therapeutics.”

“Cultural and attitude changes in the latter half of the twentieth century in many Western countries resulted in large groups of ‘mainstream’ adults and adolescents experimenting with marijuana. The scarcity of obvious acute serious toxic effects, and lack of consistent information on longer-term adverse effects has lead to more recent attitudinal changes in many Western societies that have re-opened the possibility of use of cannabis as a medication.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2544377/

Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain.

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Image result for The Journal of Supportive Oncology

“Many patients with life-threatening diseases such as cancer experience severe symptoms that compromise their health status and deny them quality of life. Patients with cancer often experience cachexia, pain, and depression,which translate into an unacceptable quality of life. The discovery of the endocannabinoid system has led to a renewed interest in the use of cannabinoids for the management of nausea, vomiting, and weight loss arising either from cancer or the agents used to treat cancer. The endocannabinoid system has been found to be a key modulator of systems involved in pain perception, emesis, and reward pathways. As such, it represents a target for development of new medications for controlling the symptoms associated with cancer. Although the cannabinoid receptor agonist tetrahydrocannabinol and one of its analogs are currently the only agents approved for clinical use, efforts are under way to devise other strategies for activating the endocannabinoid system for therapeutic uses.”

http://www.ncbi.nlm.nih.gov/pubmed/15357514

Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

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Abstract

  “The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control.”

Summary

“The discovery of an endocannabinoid signaling system has opened new possibilities for research into understanding the mechanisms of marijuana actions, the role of the endocannabinoid system in homeostasis, and the development of treatment approaches based either on the phytocannabinoids or novel molecules. CB1 agonists may have roles in the treatment of neuropathic pain, spasticity, nausea and emesis, cachexia, and potentially neuroprotection after stroke or head injury. Agonists and antagonists of peripheral CB receptors may be useful in the treatment of inflammatory and autoimmune disorders, as well as hypertension and other cardiovascular diseases. CB1 antagonists may find utility in management of obesity and drug craving. Other novel agents that may not be active at CB receptor sites, but might otherwise modify cannabinoid transport or metabolism, may also have a role in therapeutic modification of the endocannabinoid system. While the short and long term toxicities of the newer compounds are not known, one must expect that at least some of the acute effects (psychotropic effects; hypotension) may be shared by CB agonists. While there are few, long-term serious toxicities attributable to marijuana, extrapolation to newer and more potent agonists, antagonists, and cannabinoid system modulators cannot be assumed. CB1 agonists have the potential in animal models to produce drug preference and drug seeking behaviors as well as tolerance and abstinence phenomena similar to, though not generally as severe as those of other drugs of addiction. There is increasing evidence from human observations that withdrawal from the phytocannabinoids can produce an abstinence syndrome characterized primarily by irritability, sleep disturbance, mood disturbance, and appetite disturbance in chronic heavy users, therefore, such possible effects will need to be considered in the evaluation of newer shorter acting and more potent agonists.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2544377/

High hopes for new marijuana drug

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Marijuana

“Researchers have developed a synthetic compound which gives the benefits of marijuana without the high.

US researchers are developing a marijuana-derived synthetic compound to relieve pain and inflammation without the mood-altering side effects associated with other marijuana based drugs.

Professor Sumner Burstein, from the University of Massachusetts Medical School in Worcester, presented his team’s findings at last week’s national meeting of the American Chemical Society in Boston.

He is hopeful about the potential of the synthetic compound to treat a variety of conditions, including chronic pain, arthritis and Multiple Sclerosis.

The synthetic compound is called ajulemic acid, and has a formula based on that of THC. It has already produced encouraging results in animal studies of pain and inflammation, and is currently being tested on humans.

Exactly how ajulemic acid works is still under investigation but it appears to suppress chemical mediators, such as prostaglandins and cytokines, known to cause inflammation.

“We believe the compound will replace aspirin and similar drugs in most applications because of its lack of toxic side effects”, said Professor Burstein, referring to extensive animal studies, as well as a safety trial of the compound conducted in France last year among 15 healthy volunteers.

No clinically adverse effects were reported, including gastrointestinal ulcers, which have been associated with other non-steroidal anti-inflammatory compounds such as aspirin and ibuprofen.

But most significantly, no mood-altering side effects were reported. With an increasing number of medically beneficial compounds being found in marijuana, such as THC and CBD, researchers have been searching for years for ways to utilise these therapeutically without their associated “high”. They have had little success until now.

“Some people want the high,” admits Professor Burstein. “But the medical community wants efficacy without this effect.”

As well as animal studies of their own that show the compound is as potent a painkiller as morphine, Professor Burstein notes other promising animal studies that have been published. In rodent models of rheumatoid arthritis, the compound prevented joint damage. Tests of MS in rats showed the drug relieves muscle stiffness associated with the disease.

It is now undergoing tests in Germany in a group of 21 patients with chronic pain who take ajulemic acid orally twice daily, in capsule form.

Depending on these results, which will be available in about six weeks, the researchers predict the synthetic compound could be on offer by prescription within two years.

It could also be a promising alternative to current drugs used to treat arthritis, such as COX-2 inhibitors. These have been linked to adverse side effects, including heart attacks and stroke.”

http://www.abc.net.au/science/articles/2002/08/26/656786.htm?fb_action_ids=460011707368809&fb_action_types=og.likes&fb_source=aggregation&fb_aggregation_id=288381481237582

The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain.

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Abstract

“Cannabidiol, the major psycho-inactive component of cannabis, has substantial anti-inflammatory and immunomodulatory effects. This study investigated its therapeutic potential on neuropathic (sciatic nerve chronic constriction) and inflammatory pain (complete Freund’s adjuvant intraplantar injection) in rats. In both models, daily oral treatment with cannabidiol (2.5-20 mg/kg to neuropathic and 20 mg/kg to adjuvant-injected rats) from day 7 to day 14 after the injury, or intraplantar injection, reduced hyperalgesia to thermal and mechanical stimuli. In the neuropathic animals, the anti-hyperalgesic effect of cannabidiol (20 mg/kg) was prevented by the vanilloid antagonist capsazepine (10 mg/kg, i.p.), but not by cannabinoid receptor antagonists. Cannabidiol’s activity was associated with a reduction in the content of several mediators, such as prostaglandin E(2) (PGE(2)), lipid peroxide and nitric oxide (NO), and in the over-activity of glutathione-related enzymes. Cannabidiol only reduced the over-expression of constitutive endothelial NO synthase (NOS), without significantly affecting the inducible form (iNOS) in inflamed paw tissues. Cannabidiol had no effect on neuronal and iNOS isoforms in injured sciatic nerve. The compound’s efficacy on neuropathic pain was not accompanied by any reduction in nuclear factor-kappaB (NF-kappaB) activation and tumor necrosis factor alpha (TNFalpha) content. The results indicate a potential for therapeutic use of cannabidiol in chronic painful states.”

http://www.ncbi.nlm.nih.gov/pubmed/17157290

Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw.

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Abstract

“Cannabidiol, the major non-psychoactive component of marijuana, has various pharmacological actions of clinical interest. It is reportedly effective as an anti-inflammatory and anti-arthritic in murine collagen-induced arthritis.

The present study examined the anti-inflammatory and anti-hyperalgesic effects of cannabidiol, administered orally (5-40 mg/kg) once a day for 3 days after the onset of acute inflammation induced by intraplantar injection of 0.1 ml carrageenan (1% w/v in saline) in the rat. At the end of the treatment prostaglandin E2 (PGE2) was assayed in the plasma, and cyclooxygenase (COX) activity, production of nitric oxide (NO; nitrite/nitrate content), and of other oxygen-derived free radicals (malondialdehyde) in inflamed paw tissues. All these markers were significantly increased following carrageenan. Thermal hyperalgesia, induced by carrageenan and assessed by the plantar test, lasted 7 h. Cannabidiol had a time- and dose-dependent anti-hyperalgesic effect after a single injection. Edema following carrageenan peaked at 3 h and lasted 72 h; a single dose of cannabidiol reduced edema in a dose-dependent fashion and subsequent daily doses caused further time- and dose-related reductions. There were decreases in PGE2 plasma levels, tissue COX activity, production of oxygen-derived free radicals, and NO after three doses of cannabidiol. The effect on NO seemed to depend on a lower expression of the endothelial isoform of NO synthase.

 In conclusion, oral cannabidiol has a beneficial action on two symptoms of established inflammation: edema and hyperalgesia.”

http://www.ncbi.nlm.nih.gov/pubmed/14963641

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.

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Philosophical Transactions of the Royal Society B: Biological Sciences: 367 (1607)

“Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released ‘endocannabinoids’ or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive ‘multi-targeting’.”  https://www.ncbi.nlm.nih.gov/pubmed/23108552

“Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities”  http://rstb.royalsocietypublishing.org/content/367/1607/3353.long

Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain.

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Abstract

“There is a growing body of evidence to support the use of medical cannabis as an adjunct to or substitute for prescription opiates in the treatment of chronic pain. When used in conjunction with opiates, cannabinoids lead to a greater cumulative relief of pain, resulting in a reduction in the use of opiates (and associated side-effects) by patients in a clinical setting. Additionally, cannabinoids can prevent the development of tolerance to and withdrawal from opiates, and can even rekindle opiate analgesia after a prior dosage has become ineffective. Novel research suggests that cannabis may be useful in the treatment of problematic substance use. These findings suggest that increasing safe access to medical cannabis may reduce the personal and social harms associated with addiction, particularly in relation to the growing problematic use of pharmaceutical opiates. Despite a lack of regulatory oversight by federal governments in North America, community-based medical cannabis dispensaries have proven successful at supplying patients with a safe source of cannabis within an environment conducive to healing, and may be reducing the problematic use of pharmaceutical opiates and other potentially harmful substances in their communities.”

http://www.ncbi.nlm.nih.gov/pubmed/22880540