Cannabinoids, eating behaviour, and energy homeostasis.

“Soon after the discovery of cannabis by western societies, its psychotropic effects overshadowed its medical benefits. However, investigation into the molecular action of the main constituents of cannabis has led to the discovery of an intercellular signalling system, called the endocannabinoid system (ECS).

The ECS comprises a set of molecular components, including enzymes, signalling lipids and G-protein coupled receptors, which has an outstanding role in modulating eating behaviour and energy homeostasis. Interestingly, evidence has shown that the ECS is present at the central and peripheral nervous system, modulating the function of the hypothalamus, the brain reward system and the brainstem, and coordinating the crosstalk between these brain structures and peripheral organs.

Indeed, the ECS is present and functional in metabolically relevant peripheral tissues, directly modulating their physiology. In the context of a global obesity pandemic, these discoveries are highly suggestive in order to design novel pharmaceutical tools to fight obesity and related morbidities.

In fact, a cannabinoid-based first generation of drugs was developed and marketed. Their failure, due to central side-effects, is leading to a second generation of these drugs unable to cross the blood-brain barrier, as well as other ECS-focused strategies that are still in the pipeline. In the next few years we will hopefully know whether such an important player in energy homeostasis can be successfully targeted without significantly affecting other vital processes related to mood and sense of well-being.”

http://www.ncbi.nlm.nih.gov/pubmed/24375977

A potential role for GPR55 in the regulation of energy homeostasis.

“G protein-coupled receptor 55 (GPR55) is a putative cannabinoid receptor that is expressed in several tissues involved in regulating energy homeostasis, including the hypothalamus, gastrointestinal tract, pancreas, liver, white adipose and skeletal muscle.

GPR55 has been shown to have a role in cancer and gastrointestinal inflammation, as well as in obesity and type 2 diabetes mellitus (T2DM).

Despite this, the (patho)physiological role of GPR55 in cell dysfunction is still poorly understood, largely because of the limited identification of downstream signalling targets.

Nonetheless, research has suggested that GPR55 modulation would be a useful pharmacological target in metabolically active tissues to improve treatment of diseases such as obesity and T2DM.

Further research is essential to gain a better understanding of the role that this receptor might have in these and other pathophysiological conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/24370891

Chronic administration during early adulthood does not alter the hormonally-dependent disruptive effects of delta-9-tetrahydrocannabinol (Δ9-THC) on complex behavior in female rats.

“This study examined whether chronic Δ9-THC during early adulthood would produce the same hormonally-dependent deficits in learning that are produced by chronic Δ9-THC during adolescence…

no significant effects of chronic treatment and no significant interaction between the chronic treatment and cannabinoid signaling. Thus, acute Δ9-THC produced hormonally-dependent effects on learning and performance behavior, but a period of chronic administration during early adulthood did not alter these effects significantly, which is contrary to what we and others have shown for chronic administration during adolescence.”

http://www.ncbi.nlm.nih.gov/pubmed/24361784

The agonist binding mechanism of human CB2 receptor studied by molecular dynamics simulation, free energy calculation and 3D-QSAR studies.

“CB2-selective agonists have drawn attention in drug discovery, since CB2 becomes a promising target for the treatment of neuropathic pain without psychoactive or other CNS-related side effects…

A combinational exploration of both CoMFA steric and potential contour maps for CB2 affinities and the MD studied interaction modes sheds light on the structural requirements for CB2 agonists and serves as a basis for the design of novel CB2 agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/24358778

Improved Cardiac and Neurologic Outcomes With Postresuscitation Infusion of Cannabinoid Receptor Agonist WIN55, 212-2 Depend on Hypothermia in a Rat Model of Cardiac Arrest*.

“OBJECTIVES: To investigate the mechanisms of improved myocardial and neurological function and survival following IV administration of cannabinoid receptor agonist, WIN55, 212-2 in a rat model of cardiac arrest…

CONCLUSIONS: In a rat model of cardiac arrest, better postresuscitation myocardial function, neurological deficit scores, and longer duration of survival were observed by the pharmacologically induced hypothermia with WIN55, 212-2. The improved outcomes of cardiopulmonary resuscitation following administration of WIN55, 212-2 appeared to be the results from its temperature reduction effects.”

http://www.ncbi.nlm.nih.gov/pubmed/24346544

Selective CB2 receptor activation ameliorates EAE by reducing Th17 differentiation and immune cell accumulation in the CNS.

“CB2, the cannabinoid receptor expressed primarily on hematopoietic cells and activated microglia, mediates the immunoregulatory functions of cannabinoids. The involvement of CB2 in EAE has been demonstrated by using both endogenous and exogenous ligands…

the combined effect on Th17 differentiation and immune cell accumulation into the CNS, emphasize the relevance of CB2 selective ligands as potential therapeutic agents in neuroinflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/24342422

Increase of mesenchymal stem cell migration by Cannabidiol via activation of p42/44 MAPK.

“Migration and differentiation of mesenchymal stem cells (MSCs) are known to be involved in various regenerative processes such as bone healing.

The present study therefore focussed on cannabinoids which have been demonstrated to exhibit tissue healing properties…

Collectively, this study demonstrates CBD to promote the migration of MSCs via activation of the CB2 receptor and inhibition of GPR55 and to induce osteoblastic differentiation. CBD may therefore recruit MSCs to sites of calcifying tissue regeneration and subsequently support bone regeneration via an osteoanabolic action on MSCs.”

http://www.ncbi.nlm.nih.gov/pubmed/24304686

Anti-inflammatory effects of Cannabinoid 2 Receptor activation in endotoxin-induced uveitis.

“CB2 R stimulation has immunomodulatory effects. This study investigated the effects of CB2 R modulation on leukocyte-endothelial adhesion and inflammatory mediator release in experimental endotoxin-induced uveitis (EIU).

Stimulation of CB2 R is anti-inflammatory in a model of acute EIU by a mechanism involving a reduction in NF-κβ, AP-1 and inflammatory mediators.

CB2 R may be a promising drug target for the development of novel ocular anti-inflammatory agents.”

http://www.ncbi.nlm.nih.gov/pubmed/24308861

The cannabinoid receptor type 2 as mediator of mesenchymal stromal cell immunosuppressive properties.

“Recently, the presence of the endocannabinoid system in hematopoietic and neural stem cells has been demonstrated…

In the present study, we have investigated, through a multidisciplinary approach, the involvement of the endocannabinoids in migration, viability and cytokine release of human mesenchymal stromal cells.

We show, for the first time, that cultures of human mesenchymal stromal cells express all of the components of the endocannabinoid system, suggesting a potential role for the cannabinoid CB2 receptor as a mediator of anti-inflammatory properties of human mesenchymal stromal cells, as well as of their survival pathways and their capability to home and migrate towards endocannabinoid sources.”

http://www.ncbi.nlm.nih.gov/pubmed/24312195

Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction.

“AIMS: To review knowledge on cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction.

 

RESULTS AND DISCUSSION:

Components of the endocannabinoid system-cannabinoid (CB) receptor types 1 and 2, anandamide, and fatty acid amide hydrolase (FAAH), which degrades anandamide and related fatty-acid amides-have been located to lower urinary tract tissues of mice, rats, monkeys, and humans. Studies have located CB receptors in urothelium and sensory nerves and FAAH in the urothelium. CB receptor- and FAAH-related activities have also been reported in the lumbosacral spinal cord. Data on supraspinal CB functions in relation to micturition are lacking. Cannabinoids are reported to reduce sensory activity of isolated tissues, cause antihyperalgesia in animal studies of bladder inflammation, affect urodynamics parameters reflecting sensory functions in animals models, and appear to have effects on storage symptoms in humans. FAAH inhibitors have affected sensory bladder functions and reduced bladder overactivity in rat models. Cannabinoids may modify nerve-mediated functions of isolated lower urinary tract tissues.

CONCLUSIONS:

Evidence suggests components of the endocannabinoid system are involved in regulation of bladder function, possibly at several levels of the micturition pathway. It is unclear if either CB receptor has a dominant role in modification of sensory signals or if differences exist at peripheral and central nervous sites. Amplification of endocannabinoid activity by FAAH inhibitors may be an attractive drug target in specific pathways involved in LUTS.”

http://www.ncbi.nlm.nih.gov/pubmed/24285567