“Cannabinoid pharmacology has proven nettlesome with issues of promiscuity a common theme among both agonists and antagonists.
One recourse is to develop allosteric ligands to modulate cannabinoid receptor signaling.
Cannabinoids have come late to the allosteric table…
In summary, three of the allosteric modulators evaluated function in a manner consistent with allosterism in a neuronal 2-AG-based model of endogenous cannabinoid signaling.”
“Combinations of analgesics from different classes are commonly used in the management of chronic pain. The goal is to enhance pain relief together with the reduction of side effects.
The present study was undertaken to examine the anti-allodynic synergy resulting from the combination of WIN 55,212-2, a cannabinoid CB1 receptor agonist, and JTC-801, a nociceptin/orphanin FQ receptor antagonist, on neuropathic pain…
In conclusion, co-administration of acannabinoid with a nociceptin/orphanin FQ receptor antagonist resulted in a synergistic interaction, which may have utility in the pharmacological treatment of neuropathic pain.”
“Use of cannabinoids as medications has a long history.
Unfortunately, the prohibition of cannabis and its classification in 1970 as a schedule 1 drug has been a major obstacle in studying these agents in a systematic, controlled manner.
The number of class 1 studies (randomized, double-blind, placebo-controlled) in patients with movement disorders is limited. Hence, it is not possible to make recommendations on the use of these cannabinoids as primary treatments for any of the movement disorders at this time.
Fortunately, there is an expanding body of research in animal models of age-dependent and disease-related changes in the endocannabinoid system that is providing new targets for drug development.
Moreover, there is growing evidence of a “cannabinoid entourage effect” in which a combination of cannabinoids derived from the plant are more effective than any single cannabinoid for a number of conditions.
Cannabis preparations may presently offer an option for compassionate use in severe neurologic diseases, but at this point, only when standard-of-care therapy is ineffective.
As more high-quality clinical data are gathered, the therapeutic application of cannabinoids will expand.”
“The human syncytiotrophoblast (hST) has a major role in the production of important placental hormones.
Several molecules regulate hST endocrine function but the role of endocannabinoids in this process is still unknown.
Here, we report that the endocannabinoid anandamide (AEA) decreased cAMP levels, impaired human chorionic gonadotropin secretion, placental alkaline phosphatase activity and decreased aromatase mRNA levels and protein expression, through cannabinoid (CB) receptor activation.
AEA also downregulated leptin and placental protein 13 transcription, though via a CB receptor-independent mechanism.
All this evidence suggests AEA is a novel modulator of hormone synthesis by the syncytiotrophoblast, supporting the importance of the endocannabinoid signalling in placental function.”
“Corticosteroid and endocannabinoid actions converge on prefrontocortical circuits associated with neuropsychiatric illnesses. Corticosteroids can also modulate forebrain synapses by using endocannabinoid effector systems…
Altogether, corticosteroids are unlikely to exert direct non-genomic presynaptic neuromodulation in the frontal cortex, but they may do so indirectly, via the stimulation of trans-synaptic endocannabinoid signaling.”
“Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune-related disease.
Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury.
We have previously reported the receptor affinity of 3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone (SMM-189) and the characterization of the beneficial effects of SMM-189 in the mouse model of mild traumatic brain injury.
Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940.
The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined.
Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury.”
“The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumour growth, bone remodelling and bone pain.
However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here, we found that the CB2 selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micro-molar concentrations…
When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands, depending upon cell type and concentration used.
We therefore conclude that both, CB2 selective activation and antagonism have potential efficacy in cancer associated bone disease but further studies are warranted and ongoing.”
“Although exogenous cannabinoids, like those contained in marijuana, are known to exert their effects by disrupting the endocannabinoid system, a dearth of knowledge exists about the potential toxicological consequences on public health.
Conversely, the endocannabinoid system represents a promising therapeutic target for a plethora of disorders because it functions to endogenously regulate a vast repertoire of physiological functions.
Accordingly, the rapidly expanding field of cannabinoid biology has sought to leverage model organisms in order to provide both toxicological and therapeutic insights about altered endocannabinoid signaling.
The primary goal of this manuscript is to review the existing field of cannabinoid research in the genetically tractable zebrafish model-focusing on the cannabinoid receptor genes, cnr1 and cnr2, and the genes that produce enzymes for synthesis and degradation of the cognate ligands anandamide and 2-arachidonylglycerol.
Consideration is also given to research that has studied the effects of exposure to exogenous phytocannabinoids and synthetic cannabinoids that are known to interact with cannabinoid receptors.
These results are considered in the context of either endocannabinoid gene expression or endocannabinoid gene function, and are integrated with findings from rodent studies.
This provides the framework for a discussion of how zebrafish may be leveraged in the future to provide novel toxicological and therapeutic insights in the field of cannabinoid biology, which has become increasingly significant given recent trends in cannabis legislation.”
“Alpha/beta-hydrolase domain 6 (ABHD6) is a novel 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, that can fine-tune the endocannabinoid signaling in the central nervous system.
Recently we and others have demonstrated the protective effect of ABHD6 inhibition in the animal models of traumatic brain injury and epileptic seizures. In this study, we investigated the role of targeting ABHD6 in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS)…
These results suggest that inhibition of ABHD6 might be used as an ideal strategy for the treatment of MS and other neurodegenerative diseases.”
“Cannabinoid compounds usually produce biphasic effects in the modulation of emotional responses.
Low doses of the endocannabinoid anandamide (AEA) injected into the dorsolateral periaqueductal gray matter (dlPAG) induce anxiolytic-like effects via CB1 receptors activation.
However, at higher doses the drug loses this effect, in part by activating Transient Receptor Potential Vanilloid Type 1 (TRPV1).
Activation of these latter receptors could induce the formation of nitric oxide (NO). Thus, the present study tested the hypothesis that at high doses AEA loses it anxiolytic-like effect by facilitating, probably via TRPV1 receptor activation, the formation of NO.
…these results support the hypothesis that intra-dlPAG injections of high doses of AEA lose their anxiolytic effects by favoring TRPV1 receptors activity and consequent NO formation, which in turn could facilitate defensive responses.”