Tag Archives: endocannabinoid system

AM404 attenuates reinstatement of nicotine seeking induced by nicotine-associated cues and nicotine priming but does not affect nicotine- and food-taking.

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“Multiple studies suggest a pivotal role of the endocannabinoid system in the regulation of the reinforcing effects of various substances of abuse. Different approaches have been used to modulate endocannabinoid neurotransmission including the use of endogenous cannabinoid anandamide reuptake inhibitors.

 Previously, the effects of one of them, N-(4-hydroxyphenyl)-arachidonamide (AM404), have been explored in rodents trained to self-administer ethanol and heroin, producing some promising results. Moreover, AM404 attenuated the development and reinstatement of nicotine-induced conditioned place preference (CPP). In this study, we used the nicotine intravenous self-administration procedure to assess the effects of intraperitoneal administration of 0, 1, 3 and 10 mg/kg AM404 on nicotine-taking and food-taking behaviors under fixed-ratio and progressive-ratio schedules of reinforcement, as well as on reinstatement of nicotine-seeking induced by nicotine priming and by presentation of nicotine-associated cues. The ability of AM404 to produce place preference was also evaluated. AM404 did not produce CPP and did not modify nicotine-taking and food-taking behaviors. In contrast, AM404 dose-dependently attenuated reinstatement of nicotine-seeking behavior induced by both nicotine-associated cues and nicotine priming.

Our results indicate that AM404 could be a potential promising therapeutic option for the prevention of relapse to nicotine-seeking in abstinent smokers.”

http://www.ncbi.nlm.nih.gov/pubmed/23427192

Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity

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“Anecdotal evidence suggests a beneficial effect of cannabis on spasticity as well as pain. Recently, randomized, double-blind, placebo-controlled studies have confirmed the clinical efficacy of cannabinoids for the treatment of spasticity in patients with MS. Based on these data, nabiximols (Sativex), a 1:1 mix of Δ-9-tetrahydrocannabinol and cannabidiol extracted from cloned Cannabis sativa chemovars, received approval for treating MS-related spasticity in various countries around the globe. In this article we review the current understanding of cannabinoid biology and the value of cannabinoids as a symptomatic treatment option addressing spasticity in patients with MS.

Based on individual case reports, the consumption of plant parts, specifically, the resin of the Cannabis sativa hemp plant, has, for years, been attributed to the capacity to reduce the symptoms of multiple sclerosis (MS), such as spasticity, neuropathic pain, tremor, and disturbed bladder function. As characterization of the endocannabinoid system and its role in the motor system and pain processing continue to advance, there is increasing evidence of a scientific basis for the postulated therapeutic effect of cannabis derivatives.

The oromucosal administration of THC and CBD in a 1:1 ratio has proven to be a well tolerated therapeutic option for treating spasticity in patients with MS who respond poorly to conventional antispastic drugs. Assessment of the efficacy is limited by the fact that spasticity as a symptom is very difficult to measure reliably, objectively, and validly. Current study data support the position that the beneficial effects of nabiximols on subjective and objective endpoints in a selected patient sample outweigh the adverse pharmaceutical effects. The effects of long-term nabiximols treatment on neuropsychological processes and the structure of the endocannabinoid system need to be further characterized.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437528/

Endocannabinoid system modulator use in everyday clinical practice in the UK and Spain.

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“Spasticity is a disabling complication of multiple sclerosis. Some commonly used oral medications include baclofen, tizanidine, anticonvulsants and benzodiazepines, but their benefits are modest.

Sativex(®) (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain) is a unique cannabinoid-based medicine with two main active ingredients; 9-δ-tetrahydrocannabinol, which acts mainly on cannabinoid 1 receptors in the CNS and plays a key role in the modulation of spasticity and spasms, and cannabidiol, which has different properties, including minimization of the psychoactivity associated with 9-δ-tetrahydrocannabinol. Sativex is indicated for symptomatic improvement in adult patients with moderate-to-severe multiple sclerosis-related spasticity who have not responded adequately to other first- or second-line antispasticity medications, and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.

Over the past couple of years, Sativex has been approved for use in a number of European countries and ongoing postmarketing studies are evaluating the possible risks associated with Sativex treatment by systematically collecting all suspected adverse reactions that occur in patients from the start of treatment. Interim data from the UK as well as Spanish Sativex safety registries confirm that clinical benefit is maintained over the longer term despite the expected trend for deterioration owing to disease progression.

 Even after more than 2 years of use, no new safety/tolerability signals have emerged with Sativex, including no evidence of driving impairment and no relevant incidence of falls or other adverse events of concern, such as psychiatric or nervous system events.

Sativex appears to be a well-tolerated and useful add-on therapy in patients who have not achieved an adequate response with traditional antispastic agents.”

http://www.ncbi.nlm.nih.gov/pubmed/23369054

The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis

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“The ability of cannabinoids to modulate both inflammatory and degenerative neuronal damage prompted investigations on the potential benefits of such compounds in multiple sclerosis (MS) and in animal models of this disorder. Here we measured endocannabinoid levels, metabolism and binding, and physiological activities in 26 patients with MS (17 females, aged 19–43 years), 25 healthy controls and in mice with experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS.

 Our results show that MS and EAE are associated with significant alterations of the endocannabinoid system. We found that anandamide (AEA), but not 2-arachidonoylglycerol (2-AG), was increased in the CSF of relapsing MS patients. AEA concentrations were also higher in peripheral lymphocytes of these patients, an effect associated with increased synthesis and reduced degradation of this endocannabinoid. Increased synthesis, reduced degradation, and increased levels of AEA were also detected in the brains of EAE mice in the acute phase of the disease, possibly accounting for its anti-excitotoxic action in this disorder. Accordingly, neurophysiological recordings from single neurons confirmed that excitatory transmission in EAE slices is inhibited by CB1 receptor activation, while inhibitory transmission is not.

Our study suggests that targeting the endocannabinoid system might be useful for the treatment of MS.”

http://brain.oxfordjournals.org/content/130/10/2543.abstract

Cannabis and Δ(9)-tetrahydrocannabinol (THC) for weight loss?

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“Obesity is one of the highest preventable causes of morbidity and mortality in the developed world. It has been well known for a long time that exposure to cannabis produces an increase of appetite (a phenomenon referred to as the ‘munchies’).

This phenomenon led to an exploration of the role of the endocannabinoid system in the regulation of obesity and associated metabolic syndrome. This effort subsequently led to the development of a successful therapeutic approach for obesity that consisted of blocking the cannabinoid CB(1) receptors using ligands such as Rimonabant in order to produce weight loss and improve metabolic profile. Despite being efficacious, Rimonabant was associated with increased rates of depression and anxiety and therefore removed from the market.

We recently discovered that the prevalence of obesity is paradoxically much lower in cannabis users as compared to non-users and that this difference is not accounted for by tobacco smoking status and is still present after adjusting for variables such as sex and age.

 Here, we propose that this effect is directly related to exposure to the Δ(9)-tetrahydrocannabinol (THC) present in cannabis smoke. We therefore propose the seemingly paradoxical hypothesis that THC or a THC/cannabidiol combination drug may produce weight loss and may be a useful therapeutic for the treatment of obesity and its complications.”

http://www.ncbi.nlm.nih.gov/pubmed/23410498

Inhibition of endocannabinoid degradation in experimental endotoxemia reduces leukocyte adhesion and improves capillary perfusion in the gut.

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“Changes in leukocyte-endothelial and microvascular perfusion are hallmark events in inflammation. Thus, protection of the intestinal microcirculation represents a pivotal therapeutic target in systemic inflammation and sepsis.

The endocannabinoid system (ECS) modulates a number of critical homeostatic functions and has been associated with anti-inflammatory responses. Our study aimed to examine intestinal leukocyte adhesion and capillary perfusion following selective inhibition of the endocannabinoid degradation enzyme, fatty acid amide hydrolase (FAAH), in experimental sepsis (endotoxemia).

Conclusions: FAAH inhibition prevents the LPS-induced increase in leukocyte adhesion and improves the capillary perfusion of the gut. This might be mediated in part by CB2R activation.

Our study encourages further investigation into the therapeutic potential of drugs targeting the ECS in sepsis.”

More: http://www.ncbi.nlm.nih.gov/pubmed/23382309

Targeting the endocannabinoid system to limit myocardial and cerebral ischemic and reperfusion injury.

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“Coronary and carotid arterial occlusion due to thrombosis after atherosclerotic plaque rupture is the major cause of myocardial and cerebral infarction. Together these acute events represent the leading cause of death worldwide. Early reperfusion is the best method to salvage the ischemic organ; however, it leads to additional damage known as reperfusion injury. A large number of experimental studies has been performed in the past aimed at targeting individual mediators of reperfusion injury such as treatment with anti-oxidants or anti-inflammatory agents. Although many agents proved beneficial in animal models of myocardial or cerebral ischemia/reperfusion, the attempts to translate these protective effects into clinical practice were mostly disappointing. Elucidating the complex cellular and molecular mechanisms involved in ischemic cell death is crucial for the development of more efficient drugs in order to improve current treatment strategies. The aim of this review is to discuss cannabinoid and endocannabinoid-mediated effects in the pathogenesis of myocardial infarction and reperfusion injury, post-myocardial infarction remodeling, as well as ischemic stroke and reperfusion injury.

 We report experimental evidence suggesting that targeting the endocannabinoid system might evolve as a novel therapeutic concept to limit the devastating consequences of these acute vascular events through a wide variety of mechanisms, including lowering inflammation, oxidative stress, fibrosis, and excitotoxicity, and enhanced blood flow.”

http://www.ncbi.nlm.nih.gov/pubmed/21470162

Update on the Role of Cannabinoid Receptors after Ischemic Stroke

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“The endocannabinoid system is considered as a major modulator of the cerebral blood flow, neuroinflammation, and neuronal survival… Evidence from animal models and in vitro studies suggests a global protective role for cannabinoid receptors agonists in ischemic stroke…Given its potent anti-inflammatory activities on circulating leukocytes, the CB2 activation has been proven to produce protective effects against acute poststroke inflammation. In this paper, we will update evidence on different cannabinoid-triggered avenues to reduce inflammation and neuronal injury in acute ischemic stroke…

Synthetic cannabinoids have been also investigated in animal models showing an improvement of the ischemic injury in the liver, heart, and brain. Furthermore, phytocannabinoids have been also isolated from the Cannabis sativa. Since this plant contains about 80 different cannabinoids, a strong work is still needed to test all these active compounds. This delay in cannabinoid research might be also due to the very low dose of certain cannabinoids in the plant. Thus, since Δ9-tetrahydrocannabidiol (THC) and cannabidiol (CBD) represent up to 40% of the total cannabinoid mass, these compounds have been considered as the most active mediators…

The encouraging therapeutic results of this study are in partial contrast with previous case reports, suggesting a potential relationship between stroke and chronic cannabis abuse in young human beings…

We believe that the “cannabinoid” approach represents an interesting therapeutic strategy still requiring further validations to improve neurologic and inflammatory outcomes in ischemic stroke.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337695/

Modulation of Cannabinoid Receptor Activation as a Neuroprotective Strategy for EAE and Stroke

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“These results provide evidence that alteration of the activation patterns of the various cannabinoid receptors warrant consideration for future therapeutic strategies.

Interest in the medicinal use of Cannabis sativa (marijuana) has a long historical record, extending back thousands of years. In comparison to the extensive history for medicinal applications of marijuana, the existence of an “endocannabinoid system”, with important homeostatic and pathologic functions, has only recently gained appreciation. The endocannabinoid system consists of endogenously produced cannabinoids, their receptors, and the enzymes responsible for their synthesis and degradation…

Although used in ancient Greece, Rome, and China for therapeutic purposes, concern about the use of cannabinoids as a drug of abuse has dampened interest in developing the potential therapeutic benefits of these compounds. However, a better understanding of the biologic effects has led recently to an upsurge in interest for the development of therapeutic drugs through modification of the endocannabinoid system. An additional incentive was provided by the development of synthetic cannabinoid analogs and specific inhibitors of cannabinoid receptors. Several excellent reviews cover the therapeutic potential of cannabinoids….

The present review is focused on the effects of CB2 receptor activation in models of multiple sclerosis (experimental autoimmune encephalomyelitis) and stroke (middle cerebral occlusion/reperfusion).

In summary, selective CB2 receptor agonists and CB1 receptor antagonists have significant potential for neuroprotection in animal models of two devastating diseases that currently lack effective treatment options.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855650/

Role of cannabinoids and endocannabinoids in cerebral ischemia

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“The human costs of stroke are very large and growing; it is the third largest cause of death in the United States and survivors are often faced with loss of ability to function independently. There is a large need for therapeutic approaches that act to protect neurons from the injury produced by ischemia and reperfusion… 

 Overall, the available data suggest that inhibition of CB1 receptor activation together with increased CB2 receptor activation produces beneficial effects.

These studies support the hypothesis that activation of the CB1 receptor by highly efficacious, exogenous agonists during the acute phase of ischemia decreases the likelihood of the occurrence of a detrimental event at the time of ischemia and thereby reduces the amount of infarction and neuronal death long-term… A protective role of the CB1 receptor is also supported by studies…

While it is possible that the ECS will be added to the long list of neuroprotective agents that show promise in animals and do not work in humans, there are a few reasons to be optimistic about this class of drugs. First, many of the other agents did not work because they do not cross the blood brain barrier. While the considerable lipophilicity of the cannabinoids poses its own set of problems, these drugs have no problems entering the brain. Second, the ECS is multifactorial and could “cover” multiple biochemical pathways in a single drug. Third, manipulations of the ECS has been shown to be beneficial in several preclinical models. Only time and further research will answer the most important question, are the cannabinoids of therapeutic benefit in humans suffering from stroke?”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581413/