Tag Archives: cannabinoid receptors

New insights on the role of the endocannabinoid system in the regulation of energy balance.

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“Within the last 15 years, the endocannabinoid system (ECS) has emerged as a lipid signaling system critically involved in the regulation of energy balance, since it exerts a regulatory control on every aspect related to the search, the intake, the metabolism and the storage of calories.

An overactive endocannabinoid-cannabinoid type 1 (CB1) receptor signaling promotes the development of obesity, insulin resistance and dyslipidemia, representing a valuable pharmacotherapeutic target for obesity and metabolic disorders.

However, due to psychiatric side effects, the first generation of brain-penetrant CB1 receptor blockers developed as anti-obesity treatment was removed from the European market in late 2008.

Since then, recent studies have identified new mechanisms of action of the ECS in energy balance and metabolism, as well as novel ways of targeting the system that may be efficacious for the treatment of obesity and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26374449

Abnormalities in neuroendocrine stress response in psychosis: the role of endocannabinoids.

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“The aim of this article is to summarize current evidence regarding alterations in the neuroendocrine stress response system and endocannabinoid system and their relationship in psychotic disorders such as schizophrenia.

Exposure to stress is linked to the development of a number of psychiatric disorders including psychosis.

However, the precise role of stress in the development of psychosis and the possible mechanisms that might underlie this are not well understood. Recently the cannabinoid hypothesis of schizophrenia has emerged as a potential line of enquiry.

Endocannabinoid levels are increased in patients with psychosis compared with healthy volunteers; furthermore, they increase in response to stress, which suggests another potential mechanism for how stress might be a causal factor in the development of psychosis.

However, research regarding the links between stress and the endocannabinoid system is in its infancy.

Evidence summarized here points to an alteration in the baseline tone and reactivity of the hypothalamic-pituitary-adrenal (HPA) axis as well as in various components of the endocannabinoid system in patients with psychosis.

Moreover, the precise nature of the inter-relationship between these two systems is unclear in man, especially their biological relevance in the context of psychosis.

Future studies need to simultaneously investigate HPA axis and endocannabinoid alterations both at baseline and following experimental perturbation in healthy individuals and those with psychosis to understand how they interact with each other in health and disease and obtain mechanistic insight as to their relevance to the pathophysiology of schizophrenia.”

Potential Therapeutic Value of a Novel FAAH Inhibitor for the Treatment of Anxiety.

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“Anxiety disorders are among the most prevalent psychiatric diseases with high personal costs and a remarkable socio-economic burden. However, current treatment of anxiety is far from satisfactory.

Novel pharmacological targets have emerged in the recent years, and attention has focused on the endocannabinoid (eCB) system, given the increasing evidence that supports its central role in emotion, coping with stress and anxiety.

In the management of anxiety disorders, drug development strategies have left apart the direct activation of type-1 cannabinoid receptors to indirectly enhance eCB signalling through the inhibition of eCB deactivation, that is, the inhibition of the fatty acid amide hydrolase (FAAH) enzyme.

In the present study, we provide evidence for the anxiolytic-like properties of a novel, potent and selective reversible inhibitor of FAAH, ST4070, orally administered to rodents.

Altogether, ST4070 offers a promising anxiolytic-like profile in preclinical studies, although further studies are warranted to clearly demonstrate its efficacy in the clinic management of anxiety disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26360704

Anandamide mediates cognitive judgement bias in rats.

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“In the present study, we investigated the effects of acute pharmacological manipulation of the endocannabinoid (EC) system on the valence of cognitive judgement bias of rats in the ambiguous-cue interpretation (ACI) paradigm.

Our findings suggest involvement of the endocannabinoid system in the mediation of optimistic judgement bias.”

http://www.ncbi.nlm.nih.gov/pubmed/26363193

Endocannabinoid regulation of amyloid-induced neuroinflammation.

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“The modulation of endocannabinoid (EC) levels and the activation of cannabinoid receptors are seen as promising therapeutic strategies in a variety of diseases, including Alzheimer’s disease (AD).

These data reinforce the notion of a role for the EC system in neuroinflammation and open new perspectives on the relevance of modulating EC levels in the inflammed brain.”

http://www.ncbi.nlm.nih.gov/pubmed/26362942

Tetrahydrocannabivarin (THCv) reduces Default Mode Network and increases Executive Control Network Resting State Functional Connectivity in Healthy Volunteers.

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“The cannabinoid CB1 Neutral Antagonist Tetrahydrocannabivarin (THCv) has been suggested as a possible treatment for obesity but without the depressogenic side-effects of inverse antagonists such as Rimonabant.

Our findings are the first to show that treatment with the CB1 neutral antagonist THCv decreases resting state functional connectivity in the Default Mode network and increases connectivity in the Cognitive Control network and Dorsal Visual Stream network.

This effect profile suggests possible therapeutic activity of THCv for obesity where functional connectivity has been found to be altered in these regions.”

http://www.ncbi.nlm.nih.gov/pubmed/26362774

Combination cannabinoid and opioid receptor antagonists improves metabolic outcomes in obese mice.

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“This study demonstrates that the combination of rimonabant, naloxone and norBNI is effective at producing weight loss over a sustained period of time without altering performance in standardised mouse behaviour tests. Fos expression patterns offer insight into the neuroanatomical substrates subserving these physiological and behavioural changes.

These results indicate that CB1-targeted drugs for weight loss may still be feasible.”

http://www.ncbi.nlm.nih.gov/pubmed/26360587

Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis.

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“Chronic inflammation in rheumatoid arthritis (RA) is accompanied by activation of the sympathetic nervous system, which can support the immune system to perpetuate inflammation. Several animal models of arthritis already demonstrated a profound influence of adrenergic signaling on the course of RA.

Peripheral norepinephrine release from sympathetic terminals is controlled by cannabinoid receptor type 1 (CB1), which is activated by two major endocannabinoids (ECs), arachidonylethanolamine (anandamide) and 2-arachidonylglycerol.

These ECs also modulate function of transient receptor potential channels (TRPs) located on sensory nerve fibers, which are abundant in arthritic synovial tissue. TRPs not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides.

In addition, many cell types in synovial tissue express CB1 and TRPs.

In this review, we focus on CB1 and transient receptor potential vanilloid 1 (TRPV1)-mediated effects on RA since most anti-inflammatory mechanisms induced by cannabinoids are attributed to cannabinoid receptor type 2 (CB2) activation.

We demonstrate how CB1 agonism or antagonism can modulate arthritic disease.

The concept of functional antagonism with continuous CB1 activation is discussed.

Since fatty acid amide hydrolase (FAAH) is a major EC-degrading enzyme, the therapeutic possibility of FAAH inhibition is studied.

Finally, the therapeutic potential of ECs is examined since they interact with cannabinoid receptors and TRPs but do not produce central side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/26343051

High Times for Painful Blues: The Endocannabinoid System in Pain-Depression Comorbidity.

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“Depression and pain are two of the most debilitating disorders worldwide and have an estimated cooccurrence of up to 80%. Comorbidity of these disorders is more difficult to treat, associated with significant disability and impaired health-related quality of life than either condition alone, resulting in enormous social and economic cost.

Several neural substrates have been identified as potential mediators in the association between depression and pain, including neuroanatomical reorganization, monoamine and neurotrophin depletion, dysregulation of the hypothalamo-pituitary-adrenal axis, and neuroinflammation.

However, the past decade has seen mounting evidence supporting a role for the endogenous cannabinoid (endocannabinoid) system in affective and nociceptive processing, and thus, alterations in this system may play a key role in reciprocal interactions between depression and pain.

This review will provide an overview of the preclinical evidence supporting an interaction between depression and pain and the evidence supporting a role for the endocannabinoid system in this interaction.”

http://www.ncbi.nlm.nih.gov/pubmed/26342110

“The plant Cannabis sativa has been used as a medicine throughout the world for several thousand years, with reports of its use in treating painful symptoms appearing as early as 2600 BC. The principal psychoactive ingredient of Cannabis sativa, delta-9-tetrahydrocannabinol (Δ9-THC), was first identified in 1964, and subsequent studies to understand its mechanism of action led to the discovery of the endogenous cannabinoid (endocannabinoid) system… Because of the distribution of the endocannabinoid system throughout spinal and supraspinal regions, it is in a prime position to regulate neurophysiological activities such as affective and nociceptive processing… evidence suggests a prominent role for the endocannabinoid system in the interaction between depression and pain,” http://ijnp.oxfordjournals.org/content/early/2015/09/04/ijnp.pyv095.long

G protein-coupled receptor 18: A potential role for endocannabinoid signalling in metabolic dysfunction.

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“Endocannabinoids are products of dietary fatty acids that are modulated by an alteration in food intake levels.

Overweight and obese individuals have substantially higher circulating levels of the arachidonic acid-derived endocannabinoids, anandamide and 2-arachidonoyl glycerol, and show an altered pattern of cannabinoid receptor expression.

These cannabinoid receptors are part of a large family of G protein-coupled receptors (GPCRs).

GPCRs are major therapeutic targets for various diseases within the cardiovascular, neurological, gastrointestinal and endocrine systems, as well as metabolic disorders such as obesity and type 2 diabetes mellitus.

Obesity is considered a state of chronic low grade inflammation elicited by an immunological response.

Interestingly, the newly deorphanised G protein-coupled receptor GPR18, which is considered to be a putative cannabinoid receptor, is proposed to have an immunological function.

In this review, the current scientific knowledge on GPR18 is explored including its localisation, signalling pathways and pharmacology.

Importantly, the involvement of nutritional factors and potential dietary regulation of GPR18 and its (patho)physiological roles are described.

Further research on this receptor and its regulation will enable a better understanding of the complex mechanisms of GPR18 and its potential as a novel therapeutic target for treating metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26337420