Use Of Cannabinoid Receptor Agonists Research Articles

Synthetic Cannabinoid Agonist WIN 55212-2 Targets Proliferation, Angiogenesis, and Apoptosis via MAPK/AKT Signaling in Human Endometriotic Cell Lines and a Murine Model of Endometriosis.

Endometriosis (EM) is characterized by the growth of endometrium-like tissue outside the uterus, leading to chronic inflammation and pelvic pain. Lesion proliferation, vascularization, and associated inflammation are the hallmark features of EM lesions. The legalization of recreational cannabinoids has garnered interest in the patient community and is contributing to a greater incidence of self medication; however, it remains unknown if cannabinoids possess marked disease-modifying properties. In this study, we assess the effects of synthetic cannabinoid, WIN 55212-2 (WIN 55), in EM-representative in vitro and in vivo syngeneic mouse models. WIN 55 reduced proliferation and angiogenesis in vitro, via MAPK/Akt-mediated apoptosis. These findings were corroborated in a mouse model of EM, where we found reduced TRPV1 expression in the dorsal root ganglia of the EM mouse model exposed to WIN 55, suggesting reduced signaling of pain stimuli. Ultimately, these pieces of evidence support the use of cannabinoid receptor agonists as a potential therapeutic intervention for EM associated pain and inflammation.

Cannabinoid and Cannabinoid-Related Receptors in the Myenteric Plexus of the Porcine Ileum.

Simple SummaryThe endocannabinoid system (ECS) has opened the door to novel therapeutical approaches targeting cancer, pain, anxiety, stress, and inflammatory diseases. The ECS is ubiquitously expressed in almost all members of Animalia, but its precise localization outside the central nervous system is still under investigation. In this study, the localization of the main and related cannabinoid receptors in the myenteric plexus of the porcine ileum was immunohistochemically analyzed. The myenteric plexus neurons were found to be positive for cannabinoid receptor 1 (CB1R) and the cannabinoid-related receptors transient potential vanilloid receptor 1 (TRPV1), transient potential ankyrin receptor 1 (TRPA1), and serotonin receptor 5-HT1a (5-HT1aR). In addition, the ECS receptors were also located on nerve fibers, the tunica muscularis, and the endothelium. The wide distribution of cannabinoid and cannabinoid-related receptors in the myenteric plexus provides the anatomical basis for additional investigation, suggesting the possible role of the ECS in treating pathological conditions in livestock.An important piece of evidence has shown that molecules acting on cannabinoid receptors influence gastrointestinal motility and induce beneficial effects on gastrointestinal inflammation and visceral pain. The aim of this investigation was to immunohistochemically localize the distribution of canonical cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) and the cannabinoid-related receptors transient potential vanilloid receptor 1 (TRPV1), transient potential ankyrin receptor 1 (TRPA1), and serotonin receptor 5-HT1a (5-HT1aR) in the myenteric plexus (MP) of pig ileum. CB1R, TRPV1, TRPA1, and 5-HT1aR were expressed, with different intensities in the cytoplasm of MP neurons. For each receptor, the proportions of the immunoreactive neurons were evaluated using the anti-HuC/HuD antibody. These receptors were also localized on nerve fibers (CB1R, TRPA1), smooth muscle cells of tunica muscularis (CB1R, 5-HT1aR), and endothelial cells of blood vessels (TRPV1, TRPA1, 5-HT1aR). The nerve varicosities were also found to be immunoreactive for both TRPV1 and 5-HT1aR. No immunoreactivity was documented for CB2R. Cannabinoid and cannabinoid-related receptors herein investigated showed a wide distribution in the enteric neurons and nerve fibers of the pig MP. These results could provide an anatomical basis for additional research, supporting the therapeutic use of cannabinoid receptor agonists in relieving motility disorders in porcine enteropathies.

Characterizing Trends in Synthetic Cannabinoid Receptor Agonist Use from Patient Clinical Evaluations during Medical Toxicology Consultation

ABSTRACT Synthetic cannabinoid receptor agonists (SCRAs) are a new class of compounds with profound psychoactive effects and potential toxicity. This study characterizes patterns in SCRA abuse using qualitative interviews with individuals receiving medical toxicology consultation. Patients with suspected exposure to a new psychoactive substance were interviewed by medical toxicologists upon presentation for acute care. Investigators collected clinical and qualitative data including knowledge, attitudes, beliefs, and practices related to psychoactive substance use. Responses were categorized by identifying themes, and statistics were generated to describe patterns of use. Overall, 69% (86) of the 124 cases of novel psychoactive substance use entered into the registry were associated with exposure to SCRAs. Most patients (68.8%) had used SCRAs at least once before the presenting episode. 47.7% considered SCRAs to be very easy to obtain, and 44.2% reported paying for the substances while 32.6% acquired it for free. Nearly half (48.8%) of patients reported their primary reason for use was to get high; a small proportion used SCRAs to avoid testing positive on drug screening (6.9%) or as an alternative to marijuana (4.6%). Findings suggest an independent and stable culture is developing around the use of SCRAs separate from their appeal as an “undetectable” alternative to marijuana.

Localization of cannabinoid receptors CB1, CB2, GPR55, and PPARα in the canine gastrointestinal tract.

The endocannabinoid system (ECS) is composed of cannabinoid receptors, their endogenous ligands, and the enzymes involved in endocannabinoid turnover. Modulating the activity of the ECS may influence a variety of physiological and pathophysiological processes. A growing body of evidence indicates that activation of cannabinoid receptors by endogenous, plant-derived, or synthetic cannabinoids may exert beneficial effects on gastrointestinal inflammation and visceral pain. The present ex vivo study aimed to investigate immunohistochemically the distribution of cannabinoid receptors CB1, CB2, G protein-coupled receptor 55 (GPR55), and peroxisome proliferation activation receptor alpha (PPARα) in the canine gastrointestinal tract. CB1 receptor immunoreactivity was observed in the lamina propria and epithelial cells. CB2 receptor immunoreactivity was expressed by lamina propria mast cells and immunocytes, blood vessels, and smooth muscle cells. Faint CB2 receptor immunoreactivity was also observed in neurons and glial cells of the submucosal plexus. GPR55 receptor immunoreactivity was expressed by lamina propria macrophages and smooth muscle cells. PPARα receptor immunoreactivity was expressed by blood vessels, smooth muscle cells, and glial cells of the myenteric plexus. Cannabinoid receptors showed a wide distribution in the gastrointestinal tract of the dog. Since cannabinoid receptors have a protective role in inflammatory bowel disease, the present research provides an anatomical basis supporting the therapeutic use of cannabinoid receptor agonists in relieving motility disorders and visceral hypersensitivity in canine acute or chronic enteropathies.

Typology of new psychoactive substance use among the general Australian population

AimThe aim of this study was to examine the typology of Australian illicit drug consumers to determine whether those who use new psychoactive substances (NPS) differ from those using other illicit substances. MethodsData were from the 2013 National Drug Strategy Household Survey, a representative population study; analyses were limited to participants reporting past year illicit drug use (including NPS; n = 3309). Latent class analysis identified groups based on past year substance use, and a weighted multivariable, multinomial regression model was used to examine characteristics associated with group membership. ResultsSix consumer typologies were identified: cannabis consumers (46%), pharmaceutical consumers (21%), ecstasy and cocaine consumers (19%), amphetamine and cannabis consumers (7%), polysubstance consumers (6%), and inhalant consumers (2%). Sixteen participants (total sample: 0.07%; NPS consumers: 5.7%) reported exclusive NPS use. Synthetic cannabinoid receptor agonist use was highest among amphetamine and cannabis consumers and polysubstance consumers; other NPS use was highest among polysubstance consumers. Polysubstance consumers were younger than all other groups, and more likely to engage in dangerous activities while under the influence of substances, inject drugs and report hazardous alcohol consumption. Amphetamine and cannabis consumers were more likely to report trouble ceasing their drug use. ConclusionWe found no distinct profile of NPS-only consumers; however, NPS use was a marker for more problematic patterns of use. Our findings suggest that specialised NPS interventions or harm reduction messages may not be required in the Australian context; rather, they could be based upon existing responses to drug use.

Analytical confirmation of synthetic cannabinoids in a cohort of 179 presentations with acute recreational drug toxicity to an Emergency Department in London, UK in the first half of 2015

Context: Synthetic cannabinoid receptor agonists are the largest group of new psychoactive substances reported in the last decade; in this study we investigated how commonly these drugs are found in patients presenting to the Emergency Department with acute recreational drug toxicity.Methods: We conducted an observational cohort study enrolling consecutive adult patients presenting to an Emergency Department (ED) in London (UK) January–July 2015 (6 months) with acute recreational drug toxicity. Residual serum obtained from a serum sample taken as part of routine clinical care was analyzed using high-resolution accurate mass-spectrometry with liquid-chromatography (HRAM-LCMSMS). Minimum clinical data were obtained from ED medical records.Results: 18 (10%) of the 179 patient samples were positive for synthetic cannabinoid receptor agonists. The most common was 5F AKB-48 (13 samples, concentration 50–7600 pg/ml), followed by 5F PB-22 (7, 30–400 pg/mL), MDMB-CHMICA (7, 80–8000 pg/mL), AB-CHMINACA (3, 50–1800 pg/mL), Cumyl 5F-PINACA (1, 800 pg/mL) and BB-22 (1, 60 pg/mL). Only 9/18 (50%) in whom synthetic cannabinoid receptor agonists were detected self-reported synthetic cannabinoid receptor agonist use. The most common clinical features were seizures and agitation, both recorded in four (22%) individuals. Fourteen patients (78%) were discharged from the ED, one of the four admitted to hospital was admitted to critical care.Conclusions: Synthetic cannabinoid receptor agonists were found in 10% of this cohort with acute recreational drug toxicity but self-reported in only half of these. This suggests that presentations to the ED with acute synthetic cannabinoid receptor agonist toxicity may be more common than reported.

Medicinal Uses of Marijuana and Cannabinoids

ABSTRACTIn the past two decades, there has been increasing interest in the therapeutic potential of cannabis and single cannabinoids, mainly cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC). THC and cannabis products rich in THC exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). Since 1975, 140 controlled clinical trials using different cannabinoids or whole-plant preparations for the treatment of a large number of disorders and symptoms have been conducted. Results have led to the approval of cannabis-based medicines [dronabinol, nabilone, and the cannabis extract nabiximols (Sativex®, THC:CBD = 1:1)] as well as cannabis flowers in several countries. Controlled clinical studies provide substantial evidence for the use of cannabinoid receptor agonists in cancer chemotherapy induced nausea and vomiting, appetite loss and cachexia in cancer and HIV patients, neuropathic and chronic pain, and in spasticity in multiple sclerosis. In addition, there is also some evidence suggesting a therapeutic potential of cannabis-based medicines in other indications including Tourette syndrome, spinal cord injury, Crohn's disease, irritable bowel syndrome, and glaucoma. In several other indications, small uncontrolled and single-case studies reporting beneficial effects are available, for example in posttraumatic stress disorder, attention deficit hyperactivity disorder, and migraine. The most common side effects of THC and cannabis-based medicines rich in THC are sedation and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting. In recent years there is an increasing interest in the medical use of CBD, which exerts no intoxicating side effects and is usually well-tolerated. Preliminary data suggest promising effects in the treatment of anxiety disorders, schizophrenia, dystonia, and some forms of epilepsy. This review gives an overview on clinical studies which have been published over the past 40 years.

Preferential epithelial expression of type-1 cannabinoid receptor (CB1R) in the developing canine embryo.

The use of cannabinoid receptor agonists is gaining a strong interest both in human and veterinary medicine. The potential use of cannabimimetic compounds in companion animals was reviewed in 2007 for their role in tissue inflammation and pain. A better knowledge of type-1 cannabinoid receptor (CB1R) expression on the target population may help in risk management in order to prevent unwanted side effects. We used 30-days old canine embryos to describe the distribution of CB1R by means of immunohistochemistry with a commercially available antibody.CB1R immunoreactivity was mainly epithelial and included most structures of central and peripheral nervous system, inner ear, olfactory epithelium and related structures, eye and thyroid. Further investigative research on the role of the endocannabinoid system in the developmental biology field is needed, however, we show that in the canine species we must consider pregnancy as risk condition for developmental abnormalities that may arise upon the use of CB1R receptor agonists.

Use of cannabinoid receptor agonists in cancer therapy as palliative and curative agents

Cannabinoids (the active components of Cannabis sativa) and their derivatives have received renewed interest in recent years due to their diverse pharmacological activities. In particular, cannabinoids offer potential applications as anti-tumour drugs, based on the ability of some members of this class of compounds to limit cell proliferation and to induce tumour-selective cell death. Although synthetic cannabinoids may have pro-tumour effects in vivo due to their immunosuppressive properties, predominantly inhibitory effects on tumour growth and migration, angiogenesis, metastasis, and also inflammation have been described. Emerging evidence suggests that agonists of cannabinoid receptors expressed by tumour cells may offer a novel strategy to treat cancer. In this chapter we review the more recent results generating interest in the field of cannabinoids and cancer, and provide novel suggestions for the development, exploration and use of cannabinoid agonists for cancer therapy, not only as palliative but also as curative drugs.

Cannabinoids and Multiple Sclerosis

This review discusses clinical and preclinical evidence that supports the use of cannabinoid receptor agonists for the management of multiple sclerosis. In addition, it considers preclinical findings that suggest that as well as ameliorating signs and symptoms of multiple sclerosis, cannabinoid CB(1) and/or CB(2) receptor activation may suppress some of the pathological changes that give rise to these signs and symptoms. Evidence that the endocannabinoid system plays a protective role in multiple sclerosis is also discussed as are potential pharmacological strategies for enhancing such protection in the clinic.

The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB1receptor antagonism ? or inverse agonism ? as potential obesity treatment and other therapeutic use

There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Towards this end, antagonists of cannabinoid receptors have been designed through rational drug discovery efforts. Devoid of the abuse concerns that confound and impede the use of cannabinoid receptor agonists for legitimate medical purposes, investigation of the use of cannabinoid receptor antagonists as possible pharmacotherapeutic agents is currently being actively investigated. The compound furthest along this pathway is rimonabant, a selective CB(1) (cannabinoid receptor subtype 1) antagonist, or inverse agonist, approved in the European Union and under regulatory review in the United States for the treatment of obesity. This article summarizes the basic science of the endocannabinoid system and the therapeutic potential of cannabinoid receptor antagonists, with emphasis on the treatment of obesity.