“These findings, for the first time, suggest that brain CB2 receptors modulate cocaine’s rewarding and locomotor-stimulating effects, likely by a DA-dependent mechanism. Whatever the mechanisms, the present findings, for the first time, suggest that activation of brain CB2 receptors inhibits cocaine’s rewarding and psychomotor-stimulating effects, which is congruent with a rapidly expanding corpus of published reports implicating brain CB2 receptors in modulating a variety of CNS functions such as locomotion, pain, emesis, neurogenesis, and neuroprotection. This finding not only challenges current views that CB2 receptors are absent from the CNS and that CB2 receptor ligands lack CNS effects, but also suggests that brain CB2 receptors may be a novel target for the pharmacotherapy of drug abuse and addiction.” http://europepmc.org/articles/pmc3164946
Tag Archives: agonists
Brain cannabinoid CB₂ receptors modulate cocaine’s actions in mice.
“These findings, for the first time, suggest that brain CB2 receptors modulate cocaine’s rewarding and locomotor-stimulating effects, likely by a DA-dependent mechanism.
Whatever the mechanisms, the present findings, for the first time, suggest that activation of brain CB2 receptors inhibits cocaine’s rewarding and psychomotor-stimulating effects, which is congruent with a rapidly expanding corpus of published reports implicating brain CB2 receptors in modulating a variety of CNS functions such as locomotion, pain, emesis, neurogenesis, and neuroprotection.
This finding not only challenges current views that CB2 receptors are absent from the CNS and that CB2 receptor ligands lack CNS effects, but also suggests that brain CB2 receptors may be a novel target for the pharmacotherapy of drug abuse and addiction.” http://europepmc.org/articles/pmc3164946
“Marijuana Could be Used to Treat Cocaine Addiction, According to Federal Research” http://www.laweekly.com/news/marijuana-could-be-used-to-treat-cocaine-addiction-according-to-federal-research-2392363
Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection.
“The isolation and identification of the discrete plant cannabinoids in marijuana revived interest in analyzing historical therapeutic claims made for cannabis in clinical case studies and anecdotes. In particular, sources as old as the 11th and 15th centuries claimed efficacy for crude marijuana extracts in the treatment of convulsive disorders, prompting a particularly active area of preclinical research into the therapeutic potential of plant cannabinoids in epilepsy. Since that time, a large body of literature has accumulated describing the effects of several of the >100 individual plant cannabinoids in preclinical models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. We surveyed the literature for relevant reports of such plant cannabinoid effects and critically reviewed their findings. We found that acute CB1R agonism in simple models of acute seizures in rodents typically produces anti-convulsant effects whereas CB1R antagonists exert converse effects in the same models. However, when the effects of such ligands are examined in more complex models of epilepsy, epileptogenesis and neuroprotection, a less simplistic narrative emerges. Here, the complex interactions between (i) brain regions involved in a given model, (ii) relative contributions of endocannabinoid signaling to modulation of synaptic transmission in such areas, (iii) multi-target effects, (iv) cannabinoid type 1 and type 2 receptor signaling interactions and, (v) timing, (vi) duration and (vii) localization of ligand administration suggest that there is both anti-epileptic therapeutic potential and a pro-epileptic risk in up- and down-regulation of endocannabinoid signaling in the central nervous system. Factors such receptor desensitization and specific pharmacology of ligands used (e.g. full vs partial agonists and neutral antagonists vs inverse agonists) also appear to play an important role in the effects reported. Furthermore, the effects of several plant cannabinoids, most notably cannabidiol (CBD) and cannabidavarin (CBDV), in models of seizures, epilepsy, epileptogenesis, and neuroprotection are less ambiguous, and consistent with reports of therapeutically beneficial effects of these compounds in clinical studies. However, continued paucity of firm information regarding the therapeutic molecular mechanism of CBD/CBDV highlights the continued need for research in this area in order to identify as yet under-exploited targets for drug development and raise our understanding of treatment-resistant epilepsies. The recent reporting of positive results for cannabidiol treatment in two Phase III clinical trials in treatment-resistant epilepsies provides pivotal evidence of clinical efficacy for one plant cannabinoid in epilepsy. Moreover, risks and/or benefits associated with the use of unlicensed Δ9-THC containing marijuana extracts in pediatric epilepsies remain poorly understood. Therefore, in light of these paradigm-changing clinical events, the present review’s findings aim to drive future drug development for newly-identified targets and indications, identify important limitations of animal models in the investigation of plant cannabinoid effects in the epilepsies, and focuses future research in this area on specific, unanswered questions regarding the complexities of endocannabinoid signaling in epilepsy.” https://www.ncbi.nlm.nih.gov/pubmed/28190698]]>
Bladder cancer cell growth and motility implicate cannabinoid 2 receptor-mediated modifications of sphingolipids metabolism.
“The inhibitory effects demonstrated by activation of cannabinoid receptors (CB) on cancer proliferation and migration may also play critical roles in controlling bladder cancer (BC).
CB expression on human normal and BC specimens was tested by immunohistochemistry.
Human BC cells RT4 and RT112 were challenged with CB agonists and assessed for proliferation, apoptosis, and motility. Cellular sphingolipids (SL) constitution and metabolism were evaluated after metabolic labelling.
CB1-2 were detected in BC specimens, but only CB2 was more expressed in the tumour.
Both cell lines expressed similar CB2. Exposure to CB2 agonists inhibited BC growth, down-modulated Akt, induced caspase 3-activation and modified SL metabolism.
Baseline SL analysis in cell lines showed differences linked to unique migratory behaviours and cytoskeletal re-arrangements.
CB2 activation changed the SL composition of more aggressive RT112 cells by reducing (p < 0.01) Gb3 ganglioside (-50 ± 3%) and sphingosine 1-phosphate (S1P, -40 ± 4%), which ended up to reduction in cell motility (-46 ± 5%) with inhibition of p-SRC.
CB2-selective antagonists, gene silencing and an inhibitor of SL biosynthesis partially prevented CB2 agonist-induced effects on cell viability and motility.
CB2 activation led to ceramide-mediated BC cell apoptosis independently of SL constitutive composition, which instead was modulated by CB2 agonists to reduce cell motility.”
https://www.ncbi.nlm.nih.gov/pubmed/28191815
Activation of cannabinoid receptors elicits antidepressant-like effects in a mouse model of social isolation stress.
“Social isolation stress (SIS) paradigm is a chronic stress procedure able to induce profound behavioral and neurochemical changes in rodents and evokes depressive and anxiety-like behaviors. Recent studies demonstrated that the cannabinoid system plays a key role in behavioral abnormalities such as depression through different pathways; however, there is no evidence showing a relation between SIS and the cannabinoid system. This study investigated the role of the cannabinoid system in depressive-like behavior and anxiety-like behavior of IC animals. Our findings suggest that the cannabinoid system is involved in depressive-like behaviors induced by SIS. We showed that activation of cannabinoid receptors (type 1 and 2) could mitigate depression-like behavior induced by SIS in a mouse model.” https://www.ncbi.nlm.nih.gov/pubmed/28161196]]>
A selective CB2R agonist (JWH133) restores neuronal circuit after Germinal Matrix Hemorrhage in the preterm via CX3CR1+ microglia.
“Microglia play dual roles after germinal matrix hemorrhage, and the neurotrophic phenotype maybe neuroprotective.
We raise the hypothesis that a cannabinoid receptor2 agonist (JWH133) accelerates the CX3CR1+ microglia secreting neurotrophic factors and restores damaged neuronal circuit.
Overall, this study provides evidence that JWH133 promoted a neurotrophic phenotype of microglia (CX3CR1+ microglia), beyond merely alleviating microglial proliferation and inflammation.
Moreover, JWH133 restored impaired neuronal circuit, which represent a novel therapeutic strategy following GMH in clinic.”
https://www.ncbi.nlm.nih.gov/pubmed/28153531]]>
The involvement of cannabinoids and mTOR in the reconsolidation of an emotional memory in the hippocampal-amygdala-insular circuit.
“Memory reconsolidation is the process in which reactivated long-term memory becomes transiently sensitive to amnesic agents. We evaluated the ability of post reactivation administration of the mTOR inhibitor rapamycin, separately and in combination with the cannabinoid CB1/2 receptor agonist WIN55,212-2 (WIN), given systemically or specifically into the hippocampal CA1 area, basolateral amygdala (BLA) or insular cortex (IC), to reduce inhibitory avoidance fear in rats. Taken together, the results suggest that rapamycin or a combined treatment that involves blocking mTOR and activating cannabinoids may be a promising pharmacological approach for the attenuation of reactivated emotional memories, and thus, it could represent a potential treatment strategy for disorders associated with traumatic memories.” https://www.ncbi.nlm.nih.gov/pubmed/28131675]]>
Compensatory Activation of Cannabinoid CB2 Receptor Inhibition of GABA Release in the Rostral Ventromedial Medulla in Inflammatory Pain.
“The rostral ventromedial medulla (RVM) is a relay in the descending pain modulatory system and an important site of endocannabinoid modulation of pain. Our data provide evidence that CB2 receptor function emerges in the RVM in persistent inflammation and that selective CB2 receptor agonists may be useful for treatment of persistent inflammatory pain.
SIGNIFICANCE STATEMENT:
These studies demonstrate that endocannabinoid signaling to CB1 and CB2 receptors in adult rostral ventromedial medulla is altered in persistent inflammation. The emergence of CB2 receptor function in the rostral ventromedial medulla provides additional rationale for the development of CB2 receptor-selective agonists as useful therapeutics for chronic inflammatory pain.” https://www.ncbi.nlm.nih.gov/pubmed/28100744]]>Pharmacology of cannabinoids in the treatment of epilepsy.
“The use of cannabis products in the treatment of epilepsy has long been of interest to researchers and clinicians alike; however, until recently very little published data were available to support its use. This article summarizes the available scientific data of pharmacology from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including ∆9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), ∆9-tetrahydrocannabivarin (∆9-THCV), cannabidivarin (CBDV), and ∆9-tetrahydrocannabinolic acid (Δ9-THCA). It has long been known that ∆9-THC has partial agonist activity at the endocannabinoid receptors CB1 and CB2, though it also binds to other targets which may modulate neuronal excitability and neuroinflammation. The actions of Δ9-THCV and Δ9-THCA are less well understood. In contrast to ∆9-THC, CBD has low affinity for CB1 and CB2 receptors and other targets have been investigated to explain its anticonvulsant properties including TRPV1, voltage gated potassium and sodium channels, and GPR55, among others. We describe the absorption, distribution, metabolism, and excretion of each of the above mentioned compounds. Cannabinoids as a whole are very lipophilic, resulting in decreased bioavailability, which presents challenges in optimal drug delivery. Finally, we discuss the limited drug-drug interaction data available on THC and CBD. As cannabinoids and cannabis-based products are studied for efficacy as anticonvulsants, more investigation is needed regarding the specific targets of action, optimal drug delivery, and potential drug-drug interactions.” https://www.ncbi.nlm.nih.gov/pubmed/28087250]]>
[Cannabinoid applications in glaucoma].
“Glaucoma is a slowly progressive optic neuropathy that is one of the leading causes of legal blindness throughout the world. Currently there is a limited group of topical drugs for the medical treatment of glaucoma is currently limited, and research needs to be focused on new therapeutic horizons, such as the potential usefulness of the cannabinoid agonists for the treatment of glaucoma.