“Independent stimulation of either the ghrelin or endocannabinoid system promotes food intake and increases adiposity. Given the similar distribution of their receptors in feeding associated brain regions and organs involved in metabolism, it is not surprising that evidence of their interaction and its importance in modulating energy balance has emerged. This review documents the relationship between ghrelin and endocannabinoid systems within the periphery and hypothalamus (HYP) before presenting evidence suggesting that these two systems likewise work collaboratively within the ventral tegmental area (VTA) to modulate non-homeostatic feeding. Mechanisms, consistent with current evidence and local infrastructure within the VTA, will be proposed.”
Getting into the weed: the role of the endocannabinoid system in the brain-gut axis.
“The actions of cannabis are mediated by receptors that are part of an endogenous cannabinoid system.
The endocannabinoid system (ECS) consists of the naturally occurring ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the cannabinoid receptors CB1 and CB2.
The ECS is a widely distributed transmitter system that controls gut functions peripherally and centrally. It is an important physiologic regulator of gastrointestinal motility.
Polymorphisms in the gene encoding CB1 (CNR1) have been associated with some forms of irritable bowel syndrome. The ECS is involved in the control of nausea and vomiting and visceral sensation. The homeostatic role of the ECS also extends to the control of intestinal inflammation.
We review the mechanisms by which the ECS links stress and visceral pain. CB1 in sensory ganglia controls visceral sensation, and transcription of CNR1 is modified through epigenetic processes under conditions of chronic stress. These processes might link stress with abdominal pain.
The ECS is also involved centrally in the manifestation of stress, and endocannabinoid signaling reduces the activity of hypothalamic-pituitary-adrenal pathways via actions in specific brain regions-notably the prefrontal cortex, amygdala, and hypothalamus.
Agents that modulate the ECS are in early stages of development for treatment of gastrointestinal diseases. Increasing our understanding of the ECS will greatly advance our knowledge of interactions between the brain and gut and could lead to new treatments for gastrointestinal disorders.”
New review sheds light on cannabinoids anticancer mechanisms
“The palliative effects of cannabinoids on cancer-related symptoms are well established.
In fact, many drugs comprised of delta-9-tetrahydrocannabinol (THC) or its synthetic analogues are currently approved in Canada for use in the management of chemotherapy-induced nausea and vomiting, pain relief, and appetite stimulation.
While this may provide adequate treatment to the symptoms endured by cancer patients, what if cannabis can all together treat and cure cancer?
Latest discoveries on cannabinoids and their anticancer properties focus on their molecular mechanisms of action and have been discussed in a recently published review article in Current Oncology, a peer-reviewed journal (Velasco, Sanchez, & Guzman, 2016).
It is important to begin by understanding that our body possesses an endogenous cannabinoid system.”
https://news.liftcannabis.ca/2016/04/21/new-review-sheds-light-cannabinoids-anticancer-mechanisms/
“Anticancer mechanisms of cannabinoids” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791144/
Modulation of breast cancer cell viability by a cannabinoid receptor 2 agonist, JWH-015, is calcium dependent
“Cannabinoid compounds, both nonspecific as well as agonists selective for either cannabinoid receptor 1 (CB1) or cannabinoid receptor 2 (CB2), have been shown to modulate the tumor microenvironment by inducing apoptosis in tumor cells in several model systems.
The mechanism of this modulation remains only partially delineated, and activity induced via the CB1 and CB2 receptors may be distinct despite significant sequence homology and structural similarity of ligands.
The results of this work characterize the actions of a CB2-selective agonist on breast cancer cells in a syngeneic murine model representing how a clinical presentation of cancer progression and metastasis may be significantly modulated by a G-protein-coupled receptor.”
Neuroscientists discover previously unknown function of cannabinoid receptor
“Previously Unknown Function of a Cannabinoid Receptor Identified. Study could improve our insights into brain diseases.” http://neurosciencenews.com/cb2-cannabinoid-receptor-hippocampus-4147/
“In the brain, there is a delicate interplay of signaling substances and cellular activity. Scientists have now identified another key player within this ensemble. In a laboratory study they found that the ‘cannabinoid type 2 receptor’ influences information processing inside the hippocampus. The research results might help advance our understanding of schizophrenia and Alzheimer’s, say the authors.” https://www.sciencedaily.com/releases/2016/05/160502111228.htm
“The cannabinoid type 2 receptor – also called “CB2 receptor” – is a special membrane protein. Its function is to receive chemical signals that control cellular activity. “Until now, this receptor was considered part of the immune system without function in nerve cells. However, our study shows that it also plays an important role in the signal processing of the brain,” explains Professor Dietmar Schmitz, Speaker for the DZNE-Site Berlin and Director of the Neuroscience Research Center of the Charité (NWFZ/NeuroCure).” https://scienceblog.com/483935/neuroscientists-discover-previously-unknown-function-cannabinoid-receptor/
Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus
“Endocannabinoids (eCBs) exert major control over neuronal activity by activating cannabinoid receptors (CBRs).
The functionality of the eCB system is primarily ascribed to the well-documented retrograde activation of presynaptic CB1Rs.
We find that action potential-driven eCB release leads to a long-lasting membrane potential hyperpolarization in hippocampal principal cells that is independent of CB1Rs.
The hyperpolarization, which is specific to CA3 and CA2 pyramidal cells (PCs), depends on the activation of neuronal CB2Rs, as shown by a combined pharmacogenetic and immunohistochemical approach.
Upon activation, they modulate the activity of the sodium-bicarbonate co-transporter, leading to a hyperpolarization of the neuron.
CB2R activation occurred in a purely self-regulatory manner, robustly altered the input/output function of CA3 PCs, and modulated gamma oscillations in vivo.
To conclude, we describe a cell type-specific plasticity mechanism in the hippocampus that provides evidence for the neuronal expression of CB2Rs and emphasizes their importance in basic neuronal transmission.”
Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice.
“Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa plant that produces antipsychotic effects in rodents and humans.
It also reverses L-dopa-induced psychotic symptoms and improves motor function in Parkinson’s patients. This latter effect raised the possibility that CBD could have beneficial effects on motor related striatal disorders.
To investigate this possibility we evaluated if CBD would prevent catalepsy induced by drugs with distinct pharmacological mechanisms.
These findings indicate that CBD can attenuate catalepsy caused by different mechanisms (D2 blockade, NOS inhibition and CB1 agonism) via 5-HT1A receptor activation, suggesting that it could be useful in the treatment of striatal disorders.”
Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice.
“Cannabidiol (CBD) is a major non-psychoactive compound from Cannabis sativa plant.
Given that CBD reduces psychotic symptoms without inducing extrapyramidal motor side-effects in animal models and schizophrenia patients, it has been proposed to act as an atypical antipsychotic.
In addition, CBD reduced catalepsy induced by drugs with distinct pharmacological mechanisms, including the typical antipsychotic haloperidol.
Altogether, these results suggest that CBD acts in the dorsal striatum to improve haloperidol-induced catalepsy via postsynaptic 5-HT1A receptors.”
A Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group QT/QTc Study to Evaluate the Electrophysiologic Effects of THC/CBD Spray.
“Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray has proved efficacious in the treatment of spasticity in multiple sclerosis and chronic pain.
A thorough QT/QTc study was performed to investigate the effects of THC/CBD spray on electrocardiogram (ECG) parameters in compliance with regulatory requirements, evaluating the effect of a recommended daily dose (8 sprays/day) and supratherapeutic doses (24 or 36 sprays/day) of THC/CBD spray on the QT/QTc interval in 258 healthy volunteers.
The safety, tolerability, and pharmacokinetic profile of THC/CBD spray were also evaluated. Therapeutic and supratherapeutic doses of THC/CBD spray had no effect on cardiac repolarization with primary and secondary endpoints of QTcI and QTcF/QTcB, respectively, showing similar results. There was no indication of any effect on heart rate, atrioventricular conduction, or cardiac depolarization and no new clinically relevant morphological changes were observed.
Overall, 19 subjects (25.0%) in the supratherapeutic (24/36 daily sprays of THC/CBD spray) dose group and one (1.6%) in the moxifloxacin group withdrew early due to intolerable AEs. Four psychiatric serious adverse events (AEs) in the highest dose group resulted in a reduction in the surpatherapeutic dose to 24 sprays/day.
In conclusion, THC/CBD spray does not significantly affect ECG parameters. Additionally, THC/CBD spray is well tolerated at therapeutic doses with an AE profile similar to previous clinical studies.”
Mustard vesicants alter expression of the endocannabinoid system in mouse skin.
“Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation.
Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing.
Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH).
We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process.
Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin.
Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical counter measures against vesicants.”