Analgesia by intrathecal delta-9-tetrahydrocannabinol is dependent on Cav3.2 calcium channels

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“Delta-9-tetrahydrocannabinol (Δ9-THC) is known to produce systemic analgesia that involves CB1 and CB2 cannabinoid receptors. However, there is compelling evidence that Δ9-THC can potently inhibit Cav3.2T-type calcium channels which are highly expressed in dorsal root ganglion neurons and in the dorsal horn of the spinal cord. Here, we investigated whether spinal analgesia produced by Δ9-THC involves Cav3.2 channels vis a vis cannabinoid receptors. We show that spinally delivered Δ9-THC produced dose-dependent and long-lasting mechanical anti-hyperalgesia in neuropathic mice, and showed potent analgesic effects in models of inflammatory pain induced by formalin or Complete Freund’s Adjuvant (CFA) injection into the hind paw, with the latter showing no overt sex differences. The Δ9-THC mediated reversal of thermal hyperalgesia in the CFA model was abolished in Cav3.2 null mice, but was unaltered in CB1 and CB2 null animals. Hence, the analgesic effects of spinally delivered Δ9-THC are due to an action on T-type calcium channels, rather than activation of spinal cannabinoid receptors.”

https://pubmed.ncbi.nlm.nih.gov/37231418/

https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-023-01036-8

Cannabinoids as multifaceted compounds

Phytochemistry

“Since ancient times, Cannabis and its preparations have found various applications such as for medical, recreational and industrial purposes. Subsequently the 1930s, legislation in many countries has restricted its use due to its psychotropic properties. More recently, the discovery of endocannabinoid system, including new receptors, ligands, and mediators, its role in maintaining the homeostasis of the human body and the possible implication in various physiological and pathophysiological processes has also been understood. Based on this evidence, researchers were able to develop new therapeutic targets for the treatment of various pathological disorders. For this purpose, Cannabis and cannabinoids were subjected for the evaluation of their pharmacological activities. The renewed interest in the medical use of cannabis for its potential therapeutic application has prompted legislators to take action to regulate the safe use of cannabis and products containing cannabinoids. However, each country has an enormous heterogeneity in the regulation of laws. Here, we are pleased to show a general and prevailing overview of the findings regarding cannabinoids and the multiple research fields such as chemistry, phytochemistry, pharmacology and analytics in which they are involved.”

https://pubmed.ncbi.nlm.nih.gov/37196772/

https://www.sciencedirect.com/science/article/abs/pii/S0031942223001346?via%3Dihub

The Anti-Tumorigenic Role of Cannabinoid Receptor 2 in Non-Melanoma Skin Cancer

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“Five million non-melanoma skin cancers occur globally each year, and it is one of the most common malignant cancers. The dysregulation of the endocannabinoid system, particularly cannabinoid receptor 2 (CB2), is implicated in skin cancer development, progression, and metastasis. Comparing wildtype (WT) to systemic CB2 knockout (CB2-/-) mice, we performed a spontaneous cancer study in one-year old mice, and subsequently used the multi-stage chemical carcinogenesis model, wherein cancer is initiated by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). We found that aging CB2-/- mice have an increased incidence of spontaneous cancerous and precancerous skin lesions compared to their WT counterparts. In the DMBA/TPA model, CB2-/- developed more and larger papillomas, had decreased spontaneous regression of papillomas, and displayed an altered systemic immune profile, including upregulated CD4+ T cells and dendritic cells, compared to WT mice. Immune cell infiltration in the tumor microenvironment was generally low for both genotypes, although a trend of higher myeloid-derived suppressor cells was observed in the CB2-/- mice. CB2 expression in carcinogen-exposed skin was significantly higher compared to naïve skin in WT mice, suggesting a role of CB2 on keratinocytes. Taken together, our data show that endogenous CB2 activation plays an anti-tumorigenic role in non-melanoma skin carcinogenesis, potentially via an immune-mediated response involving the alteration of T cells and myeloid cells coupled with the modulation of keratinocyte activity.”

https://pubmed.ncbi.nlm.nih.gov/37175480/

“We show that endogenous CB2 activation lowers the risk for spontaneous cancer development in aging mice and papilloma development in a chemically-induced model of skin carcinogenesis. CB2 activation can modulate the systemic immune response and reduce tumorigenesis, either by an immune-mediated response involving the alteration of T cells and myeloid cells, or by the modulation of keratinocyte proliferation. This implies that CB2 could have an anti-tumorigenic role in skin cancer and serve as a potential treatment target.”

https://www.mdpi.com/1422-0067/24/9/7773

Neuronal Cannabinoid CB1 Receptors Suppress the Growth of Melanoma Brain Metastases by Inhibiting Glutamatergic Signalling

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“Melanoma is one of the deadliest forms of cancer. Most melanoma deaths are caused by distant metastases in several organs, especially the brain, the so-called melanoma brain metastases (MBMs). However, the precise mechanisms that sustain the growth of MBMs remain elusive. Recently, the excitatory neurotransmitter glutamate has been proposed as a brain-specific, pro-tumorigenic signal for various types of cancers, but how neuronal glutamate shuttling onto metastases is regulated remains unknown. Here, we show that the cannabinoid CB1 receptor (CB1R), a master regulator of glutamate output from nerve terminals, controls MBM proliferation. First, in silico transcriptomic analysis of cancer-genome atlases indicated an aberrant expression of glutamate receptors in human metastatic melanoma samples. Second, in vitro experiments conducted on three different melanoma cell lines showed that the selective blockade of glutamatergic NMDA receptors, but not AMPA or metabotropic receptors, reduces cell proliferation. Third, in vivo grafting of melanoma cells in the brain of mice selectively devoid of CB1Rs in glutamatergic neurons increased tumour cell proliferation in concert with NMDA receptor activation, whereas melanoma cell growth in other tissue locations was not affected. Taken together, our findings demonstrate an unprecedented regulatory role of neuronal CB1Rs in the MBM tumour microenvironment.”

https://pubmed.ncbi.nlm.nih.gov/37173906/

https://www.mdpi.com/2072-6694/15/9/2439

Goods and bads of endocannabinoid system as a therapeutic target: Lessons learned after 30 years

Pharmacological Reviews: 75 (3)

“The cannabis derivative marijuana is the most widely used recreational drug in the Western world, that is consumed by an estimated 83 million individuals (~3% of the world population). In recent years, there has been a marked transformation in society regarding the risk perception of cannabis, driven by its legalization and medical use in many states in the USA and worldwide.

Compelling research evidence and the FDA cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, Δ9-tetrahydrocannabinol (THC) and other plant-derived cannabinoids (phytocannabinoids). Of note, our body has a complex endocannabinoid system (ECS) – made of receptors, metabolic enzymes and transporters – that is also regulated by phytocannabinoids.

The first endocannabinoid to be discovered 30 years ago was anandamide (N-arachidonoyl-ethanolamine); since then, distinct elements of ECS have been the target of drug design programs aimed at curing (or at least slowing down) a number of human diseases, both in the central nervous system and at the periphery. Here, a critical review of our knowledge of the goods and bads of ECS as a therapeutic target are presented, in order to define the benefits of ECS-active phytocannabinoids and ECS-oriented synthetic drugs for human health.

Significance Statement The endocannabinoid system plays important roles everywhere in our body and is either involved in mediating key processes of central and peripheral diseases or represents a therapeutic target for treatment. Understanding structure, function, and pharmacology of the components of this complex system, and in particular of key receptors (like CB1R and CB2R) and metabolic enzymes (like FAAH and MAGL), will advance our understanding of endocannabinoid signaling and activity at molecular, cellular, and system levels providing new opportunities to treat patients.”

https://pubmed.ncbi.nlm.nih.gov/37164640/

https://pharmrev.aspetjournals.org/content/early/2023/05/09/pharmrev.122.000600

Impact of Cannabinoid Receptors in the Design of Therapeutic Agents against Human Ailments

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“The cannabinoid (CB) signalling cascade is widely located in the human body and is as-sociated with several pathophysiological processes. The endocannabinoid system comprises canna-binoid receptors CB1 and CB2, which belong to G-protein coupled receptors (GPCRs). CB1 recep-tors are primarily located on nerve terminals, prohibiting neurotransmitter release, whereas CB2 are present predominantly on immune cells, causing cytokine release. The activation of CB system con-tributes to the development of several diseases which might have lethal consequences, such as CNS disorders, cancer, obesity, and psychotic disorders on human health. Clinical evidence revealed that CB1 receptors are associated with CNS ailments such as Alzheimer’s disease, Huntington’s disease, and multiple sclerosis, whereas CB2 receptors are primarily connected with immune disorders, pain, inflammation, etc. Therefore, cannabinoid receptors have been proved to be promising targets in therapeutics and drug discovery. Experimental and clinical outcomes have disclosed the success sto-ry of CB antagonists, and several research groups have framed newer compounds with the binding potential to these receptors. In the presented review, we have summarized variously reported heter-ocycles with CB receptor agonistic/antagonistic properties against CNS disorders, cancer, obesity, and other complications. The structural activity relationship aspects have been keenly described along with enzymatic assay data. The specific outcomes of molecular docking studies have also been highlighted to get insights into the binding patterns of the molecules to CB receptors.”

https://pubmed.ncbi.nlm.nih.gov/37132103/

https://www.eurekaselect.com/article/131385

Phytocannabinoids as Potential Multitargeting Neuroprotectants in Alzheimer’s Disease

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“The Endocannabinoid System (ECS) is a well-studied system that influences a variety of physiological activities. It is evident that the ECS plays a significant role in metabolic activities and also has some neuroprotective properties.

In this review, we emphasize several plant-derived cannabinoids such as β-caryophyllene (BCP), Cannabichromene (CBC), Cannabigerol (CBG), Cannabidiol (CBD), and Cannabinol (CBN), which are known to have distinctive modulation abilities of ECS. In Alzheimer’s disease (AD), the activation of ECS may provide neuroprotection by modulating certain neuronal circuitry pathways through complex molecular cascades.

The present article also discusses the implications of cannabinoid receptors (CB1 and CB2) as well as cannabinoid enzymes (FAAH and MAGL) modulators in AD. Specifically, CBR1 or CB2R modulations result in reduced inflammatory cytokines such as IL-2 and IL-6, as well as a reduction in microglial activation, which contribute to an inflammatory response in neurons. Furthermore, naturally occurring cannabinoid metabolic enzymes (FAAH and MAGL) inhibit the NLRP3 inflammasome complex, which may offer significant neuroprotection.

In this review, we explored the multi-targeted neuroprotective properties of phytocannabinoids and their possible modulations, which could offer significant benefits in limiting AD.”

https://pubmed.ncbi.nlm.nih.gov/37132109/

https://www.eurekaselect.com/article/131371

Components of the Endocannabinoid System and Effects of Cannabinoids Against Bone Diseases: A Mini-Review

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“Background: The endocannabinoid system (ECS) is involved in multiple physiological processes, including appetite regulation, pain perception, motor function development, and immune response regulation. Cannabinoids have been approved for the clinical treatment of nausea and vomiting caused by cytostatic therapy or cancer chemotherapy, loss of appetite in HIV/AIDS-associated cachexia, refractory spasms induced by multiple sclerosis, chronic pain, and urinary incontinence. 

Methods: Check out the research on ECS and bone diseases in the past 20 years. 

Results: Many studies have demonstrated that endocannabinoids (eCBs) and cannabinoid receptors (CBRs) are expressed in bone and synovial tissues, playing important roles in bone metabolism. Preclinical studies using cannabis-based therapies in animal models have shown that cannabinoids (CBs) can alleviate the development of osteoarthritis (OA), prevent osteoporosis (OP), reduce cancer-induced osteolytic destruction, and improve fracture healing, highlighting the therapeutic potential of CBs for human bone diseases. 

Conclusions: The present review summarizes various components of the ECS in bone diseases and their potential as a therapeutic target.”

https://pubmed.ncbi.nlm.nih.gov/35126132/

https://www.frontiersin.org/articles/10.3389/fphar.2021.793750/full

Cannabinoid modulation of corticolimbic activation during extinction learning and fear renewal in adults with posttraumatic stress disorder

Neurobiology of Learning and Memory

“Failure to successfully extinguish fear is a hallmark of trauma-related disorders, like posttraumatic stress disorder (PTSD). PTSD is also characterized by dysfunctional corticolimbic activation and connectivity.

The endocannabinoid system is a putative system to target for rescuing these behavioral and neural deficits. In healthy adults, acute, low-dose delta-9-tetrahydrocannabinol (THC) facilitates fear extinction and increases cortico-limbic activation and connectivity in response to threat.

The present study determines the effect of acute, low-dose THC on fear-related brain activation and connectivity during fear extinction in trauma-exposed adults with (PTSD = 19) and without PTSD [trauma-exposed controls (TEC) = 26] and non-trauma-exposed [healthy controls (HC) = 26]. We used a Pavlovian fear conditioning and extinction paradigm, where we measured concurrent functional magnetic resonance imaging (fMRI) and behavioral responses (i.e., skin conductance responding and expectancy ratings). Using a randomized, double-blind, placebo-controlled design, N = 71 subjects were randomized to receive placebo (PBO, n = 37) or THC (n = 34) prior to fear extinction learning.

During early extinction learning, individuals with PTSD given THC had greater vmPFC activation than their TEC counterparts. During a test of the return of fear (i.e., renewal), HC and individuals with PTSD given THC had greater vmPFC activation compared to TEC. Individuals with PTSD given THC also had greater amygdala activation compared to those given PBO. We found no effects of trauma group or THC on behavioral fear indices during extinction learning, recall, and fear renewal.

These data suggest that low dose, oral THC can affect neural indices of fear learning and memory in adults with trauma-exposure; this may be beneficial for future therapeutic interventions seeking to improve fear extinction learning and memory.”

https://pubmed.ncbi.nlm.nih.gov/37088409/

https://www.sciencedirect.com/science/article/abs/pii/S1074742723000394?via%3Dihub

SELECTED CANNABIS TERPENES SYNERGIZE WITH THC TO PRODUCE INCREASED CB1 RECEPTOR ACTIVATION

Biochemical Pharmacology

“The cannabis plant exerts its pharmaceutical activity primarily by the binding of cannabinoids to two G protein-coupled cannabinoid receptors, CB1 and CB2. The role that cannabis terpenes play in this activation has been considered and debated repeatedly, based on only limited experimental results. In the current study we used a controlled in-vitro heterologous expression system to quantify the activation of CB1 receptors by sixteen cannabis terpenes individually, by tetrahydrocannabinol (THC) alone and by THC-terpenes mixtures. The results demonstrate that all terpenes, when tested individually, activate CB1 receptors, at about 10-50% of the activation by THC alone. The combination of some of these terpenes with THC significantly increases the activity of the CB1 receptor, compared to THC alone. In some cases, several fold. Importantly, this amplification is evident at terpene to THC ratios similar to those in the cannabis plant, which reflect very low terpene concentrations. For some terpenes, the activation obtained by THC- terpene mixtures is notably greater than the sum of the activations by the individual components, suggesting a synergistic effect. Our results strongly support a modulatory effect of some of the terpenes on the interaction between THC and the CB1 receptor. As the most effective terpenes are not necessarily the most abundant ones in the cannabis plant, reaching “whole plant” or “full spectrum” composition is not necessarily an advantage. For enhanced therapeutic effects, desired compositions are attainable by enriching extracts with selected terpenes. These compositions adjust the treatment for various desired medicinal and personal needs.”

https://pubmed.ncbi.nlm.nih.gov/37084981/

https://www.sciencedirect.com/science/article/pii/S0006295223001399?via%3Dihub