Tag Archives: cannabinoid receptors

Biosynthesis and Fate of Endocannabinoids.

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“Since the discovery of the two cannabinoid receptors, CB1 and CB2, several molecules, commonly defined as endocannabinoids, able to bind to and functionally activate these receptors, have been discovered and characterized.

Although the general thought was that the endocannabinoids were mainly derivatives of the n-6 fatty acid arachidonic acid, recent data have shown that also derivatives (ethanolamides) of n-3 fatty acids may be classified as endocannabinoids.

Whether the n-3 endocannabinoids follow the same biosynthetic and metabolic routes of the n-6 endocannabinoids is not yet clear and so warrants further investigation.

In this review, we describe the primary biosynthetic and metabolic pathways for the two well-established endocannabinoids, anandamide and 2-arachidonoylglycerol.”

http://www.ncbi.nlm.nih.gov/pubmed/26408157

Endocannabinoids and Their Pharmacological Actions.

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“The endocannabinoid system consists of G protein-coupled cannabinoid CB1 and CB2 receptors, of endogenous compounds known as endocannabinoids that can target these receptors, of enzymes that catalyse endocannabinoid biosynthesis and metabolism, and of processes responsible for the cellular uptake of some endocannabinoids.

This review presents in vitro evidence that most or all of the following 13 compounds are probably orthosteric endocannabinoids since they have all been detected in mammalian tissues in one or more investigation, and all been found to bind to cannabinoid receptors, probably to an orthosteric site: anandamide, 2-arachidonoylglycerol, noladin ether, dihomo-γ-linolenoylethanolamide, virodhamine, oleamide, docosahexaenoylethanolamide, eicosapentaenoylethanolamide, sphingosine, docosatetraenoylethanolamide, N-arachidonoyldopamine, N-oleoyldopamine and haemopressin.

In addition, this review describes in vitro findings that suggest that the first eight of these compounds can activate CB1 and sometimes also CB2 receptors and that another two of these compounds are CB1 receptor antagonists (sphingosine) or antagonists/inverse agonists (haemopressin).

Evidence for the existence of at least three allosteric endocannabinoids is also presented. These endogenous compounds appear to target allosteric sites on cannabinoid receptors in vitro, either as negative allosteric modulators of the CB1 receptor (pepcan-12 and pregnenolone) or as positive allosteric modulators of this receptor (lipoxin A4) or of the CB2 receptor (pepcan-12).

Also discussed are current in vitro data that indicate the extent to which some established or putative orthosteric endocannabinoids seem to target non-cannabinoid receptors and ion channels, particularly at concentrations at which they have been found to interact with CB1 or CB2 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/26408156

Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the conditioning and extinction of inhibitory avoidance.

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“The endocannabinoid system has recently emerged as important in the regulation of extinction learning and in the regulation of the hypothalamic-pituitary-adrenal axis.

Here, we aimed to examine the involvement of the cannabinoid CB(1) receptor in the basolateral amygdala (BLA) in inhibitory avoidance (IA) conditioning and extinction and to test whether cannabinoid activation would reverse the effects of stress on these memory processes.

Together, our findings may support a wide therapeutic application for cannabinoids in the treatment of conditions associated with the inappropriate retention of aversive memories and stress-related disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/19741114

Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress.

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“Cannabinoids have recently emerged as a possible treatment of stress- and anxiety-related disorders such as post-traumatic stress disorder (PTSD).

Here, we examined whether cannabinoid receptor activation could prevent the effects of traumatic stress on the development of behavioral and neuroendocrine measures in a rat model of PTSD…

…cannabinoids could serve as a pharmacological treatment of stress- and trauma-related disorders.

…the results extend previous findings to another stress model and to a post-trauma treatment configuration that are more relevant to clinical context and add to the growing body of data pointing to a therapeutic potential of cannabinoids for treatment of PTSD.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242307/

http://www.thctotalhealthcare.com/category/post-traumatic-stress-disorder-ptsd/

Cannabinoid receptor activation prevents the effects of chronic mild stress on emotional learning and LTP in a rat model of depression.

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“The endocannabinoid (eCB) system has recently emerged as a promising therapeutic target for the treatment of stress-related emotional disorders.

Recent data suggest that the eCB system could represent a new therapeutic target for the treatment of depression.

The findings suggest that enhancing cannabinoid signaling could represent a novel approach to the treatment of cognitive deficits that accompany stress-related depression.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924526/

http://www.thctotalhealthcare.com/category/depression-2/

Cannabinoid type-1 receptor signaling in central serotonergic neurons regulates anxiety-like behavior and sociability.

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“The endocannabinoid (eCB) system possesses neuromodulatory functions by influencing the release of various neurotransmitters, including γ-aminobutyric acid (GABA) and glutamate. A functional interaction between eCBs and the serotonergic system has already been suggested.

Previously, we showed that cannabinoid type-1 (CB1) receptor mRNA and protein are localized in serotonergic neurons of the raphe nuclei, implying that the eCB system can modulate serotonergic functions.

In order to substantiate the physiological role of the CB1 receptor in serotonergic neurons of the raphe nuclei, we generated serotonergic 5-hydroxytryptamine (5-HT) neuron-specific CB 1 receptor-deficient mice, using the Cre/loxP system with a tamoxifen-inducible Cre recombinase under the control of the regulatory sequences of the tryptophan hydroxylase 2 gene (TPH2-CreER (T2)), thus, restricting the recombination to 5-HT neurons of the central nervous system (CNS).

Applying several different behavioral paradigms, we revealed that mice lacking the CB1 receptor in serotonergic neurons are more anxious and less sociable than control littermates. Thus, we were able to show that functional CB1 receptor signaling in central serotonergic neurons modulates distinct behaviors in mice.”

http://www.ncbi.nlm.nih.gov/pubmed/26388750

In vitro and non-invasive in vivo effects of the cannabinoid-1 receptor agonist AM841 on gastrointestinal motor function in the rat.

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“Cannabinoids have been traditionally used for the treatment of gastrointestinal (GI) symptoms, but the associated central effects, through cannabinoid-1 receptors (CB1R), constitute an important drawback. Our aims were to characterize the effects of the recently developed highly potent long-acting megagonist AM841 on GI motor function and to determine its central effects in rats…

The CB1R megagonist AM841 may potently depress GI motor function in the absence of central effects. This effect may be mediated peripherally and may be useful in the treatment of GI motility disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26387676

A Cannabinoid Receptor 2 Agonist Prevents Thrombin-Induced Blood-Brain Barrier Damage via the Inhibition of Microglial Activation and Matrix Metalloproteinase Expression in Rats.

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“Thrombin mediates the life-threatening cerebral edema and blood-brain barrier (BBB) damage that occurs after intracerebral hemorrhage (ICH).

We previously found that the selective cannabinoid receptor 2 (CB2R) agonist JWH-133 reduced brain edema and neurological deficits following germinal matrix hemorrhage (GMH).

We explored whether CB2R stimulation ameliorated thrombin-induced brain edema and BBB permeability as well as the possible molecular mechanism involved.

The results demonstrated that JWH-133 administration significantly decreased thrombin-induced brain edema and reduced the number of Iba-1-positive microglia…

We demonstrated that CB2R stimulation reduced thrombin-induced brain edema and alleviated BBB damage.”

http://www.ncbi.nlm.nih.gov/pubmed/26376816

[Cannabis – therapy for the future?]

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“Despite all the progress achieved in the treatment of chronic gastrointestinal diseases, in some patients the treatment does not reach long-term optimum effectiveness. Therefore a number of patients have turned to complementary and alternative medicine (CAM).

Of the different types of CAM patients with GIT diseases tend to prefer in particular homeopathy, acupuncture and not least phytotherapy, where therapeutic use of cannabis may also be included.

The pathophysiological basis of therapeutic effect of curative cannabis has not been fully clarified so far.

Many scientists in many fields of medicine and pharmacology have been engaged in the study of effects of cannabinoids on the body since the beginning of the 20th century with the interest significantly increasing in the 1980s.

The discovery of CB receptors (1988) and endogenous molecules which activate these receptors (1992) led to the discovery of the endocannabinoid system.

Pharmacological modulation of the endogenous cannabinoid system offers new therapeutic possibilities of treatment of many illnesses and symptoms including the GIT disorders, including of nausea, vomiting, cachexia, IBS, Crohns disease and some other disorders.

Cannabinoids are attractive due to their therapeutic potential – they affect a lot of symptoms with minimum side effects.

Experience of patients with GIT disorders show that the use of cannabis is effective and helps in cases where the standard therapy fails.”

http://www.ncbi.nlm.nih.gov/pubmed/26375695

The effects of endocannabinoid receptor agonist anandamide and antagonist rimonabant on opioid analgesia and tolerance in rats.

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“The role of the cannabinoid (CB) system in the tolerance to analgesic effect of opioid remains obscure. The aim of the present study was to evaluate the effects of the endocannabinoid nonselective receptor agonist anandamide (AEA) and CB1 receptor antagonist rimonabant (SR141716) on morphine analgesia and tolerance in rats.

The findings suggested that AEA in combination with morphine produced a significant increase in expression of analgesic tolerance to morphine.

Conversely, cannabinoid receptor antagonist SR141716 attenuated morphine analgesic tolerance.

In addition, administration of AEA with morphine increased morphine analgesia.

In conclusion, we observed that the cannabinoid receptor agonist anandamide and CB1 receptor antagonist SR141716 plays a significant role in the opioid analgesia and tolerance.”

http://www.ncbi.nlm.nih.gov/pubmed/26374993