Tag Archives: endocannabinoid system

Endocannabinoid Regulation of Neuroendocrine Systems.

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“The hypothalamus is a part of the brain that is critical for sustaining life through its homeostatic control and integrative regulation of the autonomic nervous system and neuroendocrine systems. Neuroendocrine function in mammals is mediated mainly through the control of pituitary hormone secretion by diverse neuroendocrine cell groups in the hypothalamus.

Cannabinoid receptors are expressed throughout the hypothalamus, and endocannabinoids have been found to exert pronounced regulatory effects on neuroendocrine function via modulation of the outputs of several neuroendocrine systems.

Here, we review the physiological regulation of neuroendocrine function by endocannabinoids, focusing on the role of endocannabinoids in the neuroendocrine regulation of the stress response, food intake, fluid homeostasis, and reproductive function.

Cannabis sativa (marijuana) has a long history of recreational and/or medicinal use dating back to ancient times. It was used as an analgesic, anesthetic, and antianxiety herb as early as 2600 B.C.

The hedonic, anxiolytic, and mood-elevating properties of cannabis have also been cited in ancient records from different cultures. However, it was not until 1964 that the psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol, was isolated and its chemical structure determined (Gaoni & Mechoulam, 1964).”

Endocannabinoid Mechanisms Influencing Nausea.

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“One of the first recognized medical uses of Δ(9)-tetrahydrocannabinol was treatment of chemotherapy-induced nausea and vomiting.

Although vomiting is well controlled with the currently available non-cannabinoid antiemetics, nausea continues to be a distressing side effect of chemotherapy and other disorders.

Indeed, when nausea becomes conditionally elicited by the cues associated with chemotherapy treatment, known as anticipatory nausea (AN), currently available antiemetics are largely ineffective.

Considerable evidence demonstrates that the endocannabinoid system regulates nausea in humans and other animals.

In this review, we describe recent evidence suggesting that cannabinoids and manipulations that enhance the functioning of the natural endocannabinoid system are promising treatments for both acute nausea and AN.”

The Endocannabinoid System and Its Role in Regulating the Intrinsic Neural Circuitry of the Gastrointestinal Tract.

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“Endocannabinoids are important neuromodulators in the central nervous system.

They regulate central transmission through pre- and postsynaptic actions on neurons and indirectly through effects on glial cells.

Cannabinoids (CBs) also regulate neurotransmission in the enteric nervous system (ENS) of the gastrointestinal (GI) tract.

The ENS consists of intrinsic primary afferent neurons, interneurons, and motor neurons arranged in two ganglionated plexuses which control all the functions of the gut.

Increasing evidence suggests that endocannabinoids are potent neuromodulators in the ENS.

In this review, we will highlight key observations on the localization of CB receptors and molecules involved in the synthesis and degradation of endocannabinoids in the ENS.

We will discuss endocannabinoid signaling mechanisms, endocannabinoid tone and concepts of CB receptor metaplasticity in the ENS. We will also touch on some examples of enteric neural signaling in relation neuromuscular, secretomotor, and enteroendocrine transmission in the ENS. Finally, we will briefly discuss some key future directions.”

The Endocannabinoid Signaling System in the CNS: A Primer.

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“The purpose of this chapter is to provide an introduction to the mechanisms for the regulation of endocannabinoid signaling through CB1 cannabinoid receptors in the central nervous system.

The processes involved in the synthesis and degradation of the two most well-studied endocannabinoids, 2-arachidonoylglycerol and N-arachidonylethanolamine are outlined along with information regarding the regulation of the proteins involved.

Signaling mechanisms and pharmacology of the CB1 cannabinoid receptor are outlined, as is the paradigm of endocannabinoid/CB1 receptor regulation of neurotransmitter release.

The reader is encouraged to appreciate the importance of the endocannabinoid/CB1 receptor signaling system in the regulation of synaptic activity in the brain.”

Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants.

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“Cannabis and analogs of Δ9-tetrahydrocannabinol have been used for therapeutic purposes…

Endogenous cannabinoids have been discovered, and dysregulation of endocannabinoid signaling is implicated in the pathophysiology of major depressive disorder (MDD).

Recently, endocannabinoid hydrolytic enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have become new therapeutic targets in the treatment of MDD.

Several FAAH or MAGL inhibitors are reported to have no cannabimimetic side effects and, therefore, are new potential therapeutic options for patients with MDD who are resistant to first-line antidepressants (selective serotonin and serotonin-norepinephrine reuptake inhibitors).

In this review, we focus on the possible relationships between MDD and the endocannabinoid system as well as the inhibitors’ therapeutic potential.

MAGL inhibitors may reduce inflammatory responses through activation of cannabinoid receptor type 2.

In the hypothalamic-pituitary-adrenal axis, repeated FAAH inhibitor administration may be beneficial for reducing circulating glucocorticoid levels. Both FAAH and MAGL inhibitors may contribute to dopaminergic system regulation. Recently, several new inhibitors have been developed with strong potency and selectivity. FAAH inhibitor, MAGL inhibitor, or dual blocker use would be promising new treatments for MDD. Further pre-clinical studies and clinical trials using these inhibitors are warranted.”

http://www.ncbi.nlm.nih.gov/pubmed/26630956

CB1 cannabinoid receptor enrichment in the ependymal region of the adult human spinal cord

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Figure 1

“Cannabinoids are involved in the regulation of neural stem cell biology and their receptors are expressed in the neurogenic niches of adult rodents.

In the spinal cord of rats and mice, neural stem cells can be found in the ependymal region, surrounding the central canal, but there is evidence that this region is largely different in adult humans: lacks a patent canal and presents perivascular pseudorosettes, typically found in low grade ependymomas.

Using Laser Capture Microdissection, Taqman gene expression assays and immunohistochemistry, we have studied the expression of endocannabinoid system components (receptors and enzymes) at the human spinal cord ependymal region.

We observe that ependymal region is enriched in CB1 cannabinoid receptor, due to high CB1 expression in GFAP+ astrocytic domains. However, in human spinal cord levels that retain central canal patency we found ependymal cells with high CB1 expression, equivalent to the CB1HIGH cell subpopulation described in rodents.

Our results support the existence of ependymal CB1HIGH cells across species, and may encourage further studies on this subpopulation, although only in cases when central canal is patent. In the adult human ependyma, which usually shows central canal absence, CB1 may play a different role by modulating astrocyte functions.”

http://www.nature.com/articles/srep17745

Prevention of Diet-Induced Obesity Effects on Body Weight and Gut Microbiota in Mice Treated Chronically with Δ9-Tetrahydrocannabinol.

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“Acute administration of cannabinoid CB1 receptor agonists, or the ingestion of cannabis, induces short-term hyperphagia. However, the incidence of obesity is lower in frequent cannabis users compared to non-users.

Gut microbiota affects host metabolism and altered microbial profiles are observed in obese states. Gut microbiota modifies adipogenesis through actions on the endocannabinoid system. This study investigated the effect of chronic THC administration on body weight and gut microbiota in diet-induced obese (DIO) and lean mice.

THC reduced weight gain, fat mass gain and energy intake in DIO but not lean mice. DIO-induced changes in select gut microbiota were prevented in mice chronically administered THC.

Chronic THC treatment reduced energy intake and prevented high fat diet-induced increases in body weight and adiposity; effects that were unlikely to be a result of sedation or altered gastrointestinal transit. Changes in gut microbiota potentially contribute to chronic THC-induced actions on body weight in obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/26633823

“Prevention of Diet-Induced Obesity Effects on Body Weight and Gut Microbiota in Mice Treated Chronically with Δ9-Tetrahydrocannabinol… To follow up on our hypothesis that exposure to THC may produce weight loss, in the current study we investigated whether chronic THC inhibits weight gain in lean and diet-induced obese (DIO) mice… We present data showing that chronic administration of the CB1/CB2 receptor partial agonist, THC, prevents weight gain in DIO mice. Furthermore, we show evidence that DIO-mediated modifications in gut microbiota are prevented in chronically THC treated mice… In conclusion, we present data showing the CB1/CB2 receptor partial agonist THC, induces hypophagia and prevents weight gain in obesity and suggest these actions may be mediated in part by modifications of the gut microbiota.”  http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144270

Liver’s cannabinoid receptors could be targeted to combat liver cancer in some patients

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News Medical - Life Sciences & Medicine

“A new study reveals that the liver’s cannabinoid receptors could be targeted to fight liver cancer in some patients; and it offers a way to predict what treatments have the best chance of working.

The body’s own marijuana-like substances, — called endocannabinoids — are known to increase the biosynthesis of fatty acids in the liver by activating cannabinoid type 1 receptors (CB1). CB1 receptors can be found in the brain, lungs, liver and kidney, and they are involved in a number of physiological processes, including mood, appetite, pain sensation and memory.

The study found that the expression of these receptors increased in cancerous liver samples, when compared with cancer-free samples. This suggests that drugs that block CB1 receptors may be effective against HCC.

“Although such drugs were found to cause unwanted psychiatric side effects, non brain-penetrant CB1 receptor antagonists devoid of such side effects — but retaining therapeutic efficacy via peripheral CB1 receptors — are currently being developed,” says study co-author George Kunos, scientific director at the U.S. National Institute on Alcohol Abuse and Alcoholism (NIAAA).”

http://www.news-medical.net/news/20151123/Livers-cannabinoid-receptors-could-be-targeted-to-combat-liver-cancer-in-some-patients.aspx

The endocannabinoid system as a target for the treatment of neuronal damage.

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“Cannabinoids have been proposed as clinically promising neuroprotective molecules, based on their capability to normalize glutamate homeostasis, reducing excitotoxicity, to inhibit calcium influx, lowering intracellular levels and the subsequent activation of calcium-dependent destructive pathways, and to reduce the generation of reactive oxygen intermediates or to limit their toxicity, decreasing oxidative injury.

Cannabinoids are also able to decrease local inflammatory events by acting on glial processes that regulate neuronal survival, and to restore blood supply by reducing vasocontriction produced by several endothelium-derived factors.

Treatment of neurodegenerative disorders is a challenge for neuroscientists and neurologists. Unhappily, the efficacy of available medicines is still poor and there is an urgent need for novel neuroprotective agents. Cannabinoids can serve this purpose given their recognized antiexcitotoxic, antioxidant and anti-inflammatory properties.”

http://www.ncbi.nlm.nih.gov/pubmed/20230193

The endocannabinoid system in guarding against fear, anxiety and stress.

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“The endocannabinoid (eCB) system has emerged as a central integrator linking the perception of external and internal stimuli to distinct neurophysiological and behavioural outcomes (such as fear reaction, anxiety and stress-coping), thus allowing an organism to adapt to its changing environment.

eCB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism’s long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders.

An understanding of the underlying neural cell populations and cellular processes enables the development of therapeutic strategies to mitigate behavioural maladaptation.”

http://www.ncbi.nlm.nih.gov/pubmed/26585799