“The cannabinoid 2 receptor (CB2R) is a promising anti-inflammatory drug target and development of selective CB2R ligands may be useful for treating sight-threatening ocular inflammation. This study examined the pharmacology of three novel chemically-diverse selective CB2R ligands. These unique ligands are potent and selective for CB2R and have good immunomodulating actions in the eye. The data generated with these three structurally-diverse and highly-selective CB2R agonists support selective targeting of CB2R for treating ocular inflammatory diseases.”
https://www.ncbi.nlm.nih.gov/pubmed/31540271
https://www.mdpi.com/1420-3049/24/18/3338
Category Archives: Endocannabinoid System
Druggable Targets of the Endocannabinoid System: Implications for the Treatment of HIV-Associated Neurocognitive Disorder.
“HIV-associated neurocognitive disorder (HAND) affects nearly half of all HIV-infected individuals. Synaptodendritic damage correlates with neurocognitive decline in HAND, and many studies have demonstrated that HIV-induced neuronal injury results from excitotoxic and inflammatory mechanisms.
The endocannabinoid (eCB) system provides on-demand protection against excitotoxicity and neuroinflammation.
Here, we discuss evidence of the neuroprotective and anti-inflammatory properties of the eCB system from in vitro and in vivo studies. We examine the pharmacology of the eCB system and evaluate the therapeutic potential of drugs that modulate eCB signaling to treat HAND.
Finally, we provide perspective on the need for additional studies to clarify the role of the eCB system in HIV neurotoxicity and speculate that strategies that enhance eCB signaling might slow cognitive decline in HAND.”
https://www.ncbi.nlm.nih.gov/pubmed/31539547
https://www.sciencedirect.com/science/article/abs/pii/S0006899319305219?via%3Dihub
The Impact of Cannabinoid Receptor 2 Deficiency on Neutrophil Recruitment and Inflammation.
“Neutrophil trafficking into damaged or infected tissues is essential for the initiation of inflammation, clearance of pathogens and damaged cells, and ultimately tissue repair. Neutrophil recruitment is highly dependent on the stepwise induction of adhesion molecules and promigratory chemokines and cytokines.
A number of studies in animal models have shown the efficacy of cannabinoid receptor 2 (CB2) agonists in limiting inflammation in a range of preclinical models of inflammation, including colitis, atherosclerosis, multiple sclerosis, and ischemia-reperfusion injury.
Recent work in preclinical models of inflammation raises two questions: by what mechanisms do CB2 agonists provide anti-inflammatory effects during acute inflammation and what challenges exist in the translation of CB2 modulating therapeutics into the clinic.”
The Endocannabinoid System of Animals.
“The endocannabinoid system has been found to be pervasive in mammalian species. It has also been described in invertebrate species as primitive as the Hydra. Insects, apparently, are devoid of this, otherwise, ubiquitous system that provides homeostatic balance to the nervous and immune systems, as well as many other organ systems.
The endocannabinoid system (ECS) has been defined to consist of three parts, which include (1) endogenous ligands, (2) G-protein coupled receptors (GPCRs), and (3) enzymes to degrade and recycle the ligands. Two endogenous molecules have been identified as ligands in the ECS to date.
The endocannabinoids are anandamide (arachidonoyl ethanolamide) and 2-AG (2-arachidonoyl glycerol). Two G-coupled protein receptors (GPCR) have been described as part of this system, with other putative GPC being considered.
Coincidentally, the phytochemicals produced in large quantities by the Cannabis sativa L plant, and in lesser amounts by other plants, can interact with this system as ligands. These plant-based cannabinoids are termed phytocannabinoids.
The precise determination of the distribution of cannabinoid receptors in animal species is an ongoing project, with the canine cannabinoid receptor distribution currently receiving the most interest in non-human animals.”
Insights into the role of cannabis in the management of inflammatory bowel disease.
“Cannabis, a drug made up of the flowers and buds of the Cannabis sativa plant, has been used therapeutically for centuries. Ancient Chinese cultures have reported use in their medical practices, dating back as early as 2700 BC. Although widely used recreationally during the 19th and 20th centuries, the use of medical cannabis has exploded over the last decade, as a result of mainstream cultural acceptance and legalization in several countries around the world.
Over the last decade, interest in the therapeutic potential of cannabis and its constituents (e.g. cannabidiol) in the management of inflammatory bowel diseases (IBD) has escalated. Cannabis has been increasingly approved for a variety of medical conditions in several jurisdictions around the world.
In animal models, cannabinoids have been shown to improve intestinal inflammation in experimental models of IBD through their interaction with the endocannabinoid system. However, the few randomized controlled trials of cannabis or cannabidiol in patients with IBD have not demonstrated efficacy in modulating inflammatory disease activity.
Cannabis may be effective in the symptomatic management of IBD. Given the increasing utilization and cultural acceptance of cannabis, physicians need to be aware of its safety and efficacy in order to better counsel patients. The aim of this review is to provide an overview of the role of cannabis in the management of patients with IBD.
There is emerging evidence that cannabis may play a role in the management of patients with IBD. Many patients are already using cannabis to help manage symptoms associated with the disease, and physicians cannot ignore this when taking histories and managing their patients.”
Cannabinoids in Gynecological Diseases
“The endocannabinoid system (ECS) is a multifunctional homeostatic system involved in many physiological and pathological conditions. The ligands of the ECS are the endocannabinoids, whose actions are mimicked by exogenous cannabinoids, such as phytocannabinoids and synthetic cannabinoids. Responses to the ligands of the ECS are mediated by numerous receptors like the classical cannabinoid receptors (CB1 and CB2) as well as ECS-related receptors, e.g., G protein-coupled receptors 18 and 55 (GPR18 and GPR55), transient receptor potential ion channels, and nuclear peroxisome proliferator-activated receptors. The ECS regulates almost all levels of female reproduction, starting with oocyte production through to parturition. Dysregulation of the ECS is associated with the development of gynecological disorders from fertility disorders to cancer. Cannabinoids that act at the ECS as specific agonists or antagonists may potentially influence dysregulation and, therefore, represent new therapeutic options for the therapy of gynecological disorders.”
Modulation of the endocannabinoid system: vulnerability factor and new treatment target for stimulant addiction
“Interestingly, increasing recent evidence points toward the involvement of the endocannabinoid system (ECBS) in the neurobiological processes related to stimulant addiction.
This article presents an up-to-date review with deep insights into the pivotal role of the ECBS in the neurobiology of stimulant addiction and the effects of its modulation on addictive behaviors. This article aims to: (1) review the role of cannabis use and ECBS modulation in the neurobiological substrates of psychostimulant addiction and (2) evaluate the potential of cannabinoid-based pharmacological strategies to treat stimulant addiction.
A growing number of studies support a critical role of the ECBS and its modulation by synthetic or natural cannabinoids in various neurobiological and behavioral aspects of stimulants addiction. Thus, cannabinoids modulate brain reward systems closely involved in stimulants addiction, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for treating addiction across different classes of stimulants.
Interestingly, emerging human data supports a role for ECBS modulation in vulnerability to psychostimulant addiction, and more significantly in addictive behaviors among dependent individuals. Accumulating evidence thus points to the ECBS as a critical target for the development of pharmacotherapies for the treatment of addiction to psychostimulants.
Given the various neuropharmacological actions of exogenous cannabinoids, and their ability to modulate the acute reinforcing effects of drugs, data on Δ9-THC and CBD is particularly promising as to the potential use of cannabinoids in relapse prevention strategies for psychostimulant-dependent individuals.”
https://www.frontiersin.org/articles/10.3389/fpsyt.2013.00109/full
Endocannabinoid modulation of inflammatory hyperalgesia in the IFN-α mouse model of depression.
“Depression is a well-recognised effect of long-term treatment with interferon-alpha (IFN-α), a widely used treatment for chronic viral hepatitis and malignancy. In addition to the emotional disturbances, high incidences of painful symptoms such as headache and joint pain have also been reported following IFN-α treatment.
The endocannabinoid system plays an important role in emotional and nociceptive processing, however it is unknown whether repeated IFN-α administration induces alterations in this system.
The present study investigated nociceptive responding in the IFN-α-induced mouse model of depression and associated changes in the endocannabinoid system. Furthermore, the effects of modulating peripheral endocannabinoid tone on inflammatory pain-related behaviour in the IFN-α model was examined.
In summary, increasing peripheral endocannabinoid tone attenuates inflammatory hyperalgesia induced following repeated IFN-α administration. These data provide support for the endocannabinoid system in mediating and modulating heightened pain responding associated with IFNα-induced depression.”
https://www.ncbi.nlm.nih.gov/pubmed/31505257
“Inflammatory hyperalgesia is associated with altered endocannabinoid levels. Enhancing peripheral endocannabinoid tone attenuates IFN-α related hyperalgesia.”
https://www.sciencedirect.com/science/article/pii/S0889159119306063?via%3Dihub
The “entourage effect”: Terpenes coupled with cannabinoids for the treatment of mood disorders and anxiety disorders.
“Mood disorders are the most prevalent mental conditions encountered in psychiatric practice. Numerous patients suffering from mood disorders present with treatment-resistant forms of depression, co-morbid anxiety, other psychiatric disorders and bipolar disorders.
Standardized essential oils (such as that of Lavender officinalis) have been shown to exert clinical efficacy in treating anxiety disorders. As endocannabinoids are suggested to play an important role in major depression, generalized anxiety and bipolar disorders, Cannabis sativa, was suggested for their treatment.
The endocannabinoid system is widely distributed throughout the body including the brain, modulating many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids.
CB1 and CB2 receptors primarily serve as the binding sites for endocannabinoids as well as for phytocannabinoids, produced by cannabis inflorescences. However, ‘cannabis’ is not a single compound product but is known for its complicated molecular profile, producing a plethora of phytocannabinoids alongside a vast array of terpenes.
Thus, the “entourage effect” is the suggested positive contribution derived from the addition of terpenes to cannabinoids. Here we review the literature on the effects of cannabinoids and discuss the possibility of enhancing cannabinoid activity on psychiatric symptoms by the addition of terpenes and terpenoids.
Possible underlying mechanisms for the anti-depressant and anxiolytic effects are reviewed. These natural products may be an important potential source for new medications for the treatment of mood and anxiety disorders.”
Insights into biased signaling at cannabinoid receptors: synthetic cannabinoid receptor agonists.
“Cannabinoid receptors type 1 (CB1) and type 2 (CB2) are promising targets for a number of diseases, including obesity, neuropathic pain, and multiple sclerosis, among others.
Upon ligand-mediated activation of these receptors, multiple receptor conformations could be stabilized, resulting in a complex pattern of possible intracellular effects. Although numerous compounds have been developed and widely used to target cannabinoid receptors, their mode of action and signaling properties are often only poorly characterized.
From a drug development point of view, unraveling the underlying complex signaling mechanism could offer the possibility to generate medicines with the desired therapeutic profile.
Recently, an increased interest has emerged for the development of agonists that are signaling pathway-selective and thereby do not evoke on-target adverse effects. This phenomenon, in which specific pathways are preferred upon receptor activation by certain ligands, is also known as ‘biased signaling’.
For a particular group of cannabinoid receptor ligands (i.e. CB1/CB2 agonists), namely the synthetic cannabinoid receptor agonists (SCRAs), the research on biased signaling is still in its infancy and interesting outcomes are only recently being revealed.
Therefore, this review aims at providing insights into the recent knowledge about biased agonism mediated by SCRAs so far. In addition, as these outcomes are obtained using a distinct panel of functional assays, the accompanying difficulties and challenges when comparing functional outcomes are critically discussed. Finally, some guidance on the conceptualization of ideal in vitro assays for the detection of SCRA-mediated biased agonism, which is also relevant for compounds belonging to other chemical classes, is provided.”
https://www.ncbi.nlm.nih.gov/pubmed/31472128
https://www.sciencedirect.com/science/article/abs/pii/S0006295219303132?via%3Dihub