Components of the Endogenous Cannabinoid System as Potential Biomarkers for Interstitial Cystitis/Bladder Pain Syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition causing bladder pressure and pain. The condition is of unknown etiology and is often accompanied by other symptoms, including chronic pelvic pain, increased urinary urgency, and frequency. There is no definitive diagnosis for IC/BPS, and treatment options are currently limited to physical therapy and medications to help alleviate symptoms. The endogenous cannabinoid system (ECS) is an important regulator of numerous physiological systems, including the urinary system. Modulations of the ECS have been shown to be beneficial for IC/BPS-associated pain and inflammation in rodents. As an attempt to identify potential biomarkers for IC/BPS, we reviewed experimental studies where the components of the ECS have been quantified in experimental models of IC/BPS. Further investigations using well-defined animal models and patients’ data are required to obtain stronger evidence regarding the potential for ECS components to be definitive biomarkers for IC/BPS.

Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1

Background and purpose: Anxiety is often characterized by an inability to extinguish learned fear responses. Orexins/hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may contribute to the aetiology of anxiety disorders characterized by pathological fear. The mechanisms by which orexins regulate fear remain unknown. Experimental approach: We investigated the role of the endogenous cannabinoid system in the impaired fear extinction induced by orexin-A (OXA) in male mice. Behavioural pharmacology, neurochemical, molecular and genetic approaches were used. Key results: The selective inhibitor of 2-arachidonoylglycerol (2-AG) biosynthesis O7460 abolished the fear extinction deficits induced by OXA. Accordingly, increased 2-AG levels were observed in the amygdala and hippocampus of mice treated with OXA that do not extinguish fear, suggesting that high levels of this endocannabinoid are related to poor extinction. Impairment of fear extinction induced by OXA was associated with increased expression of CB2 cannabinoid receptor (CB2R) in microglial cells of the basolateral amygdala. Consistently, the intra-amygdala infusion of the CB2R antagonist AM630 completely blocked the impaired extinction promoted by OXA. Microglial and CB2R expression depletion in the amygdala with PLX5622 chow also prevented these extinction deficits. Conclusions and implications: We reveal that overactivation of the orexin system leads to impaired fear extinction through 2-AG and amygdalar CB2R. This novel mechanism may pave the way towards novel potential approaches to treat diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder, panic anxiety and phobias.

Cannabinoid Drugs-Related Neuroprotection as a Potential Therapeutic Tool Against Chemotherapy-Induced Cognitive Impairment

In recent years, and particularly associated with the increase of cancer patients’ life expectancy, the occurrence of cancer treatment sequelae, including cognitive impairments, has received considerable attention. Chemotherapy-induced cognitive impairments (CICI) can be observed not only during pharmacological treatment of the disease but also long after cessation of this therapy. The lack of effective tools for its diagnosis together with the limited treatments currently available for alleviation of the side-effects induced by chemotherapeutic agents, demonstrates the need of a better understanding of the mechanisms underlying the pathology. This review focuses on the comprehensive appraisal of two main processes associated with the development of CICI: neuroinflammation and oxidative stress, and proposes the endogenous cannabinoid system (ECS) as a new therapeutic target against CICI. The neuroprotective role of the ECS, well described in other cognitive-related neuropathologies, seems to be able to reduce the activation of pro-inflammatory cytokines involved in the neuroinflammatory supraspinal processes underlying CICI. This review also provides evidence supporting the role of cannabinoid-based drugs in the modulation of oxidative stress processes that underpin cognitive impairments, and warrant the investigation of endocannabinoid components, still unknown, that may mediate the molecular mechanism behind this neuroprotective activity. Finally, this review points forward the urgent need of research focused on the understanding of CICI and the investigation of new therapeutic targets.

The Effects of Repeated Morphine Treatment on the Endogenous Cannabinoid System in the Ventral Tegmental Area

The therapeutic utility of opioids is diminished by their ability to induce rewarding behaviors that may lead to opioid use disorder. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how repeated opioid exposure may affect the endogenous cannabinoid system in the mesolimbic reward circuitry. In the present study, we investigated how sustained morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA) of Sprague Dawley rats, a critical region in the mesolimbic reward circuitry. Studies here using proteomic analysis and quantitative real-time PCR (qRT-PCR) found that the VTA expresses 32 different proteins or genes related to the endogenous cannabinoid system; three of these proteins or genes (PLCγ2, ABHD6, and CB2R) were significantly affected after repeated morphine exposure (CB2R was only detected by qRT-PCR but not proteomics). We also identified that repeated morphine treatment does not alter either anandamide (AEA) or 2-arachidonoylglycerol (2-AG) levels in the VTA compared to saline treatment; however, there may be diminished levels of anandamide (AEA) production in the VTA 4 h after a single morphine injection in both chronic saline and morphine pretreated cohorts. Treating the animals with an inhibitor of 2-AG degradation significantly decreased repeated opioid rewarding behavior. Taken together, our studies reveal a potential influence of sustained opioids on the endocannabinoid system in the VTA, suggesting that the endogenous cannabinoid system may participate in the opioid-induced reward.

Cannabidiol or CBD Oil: Help, Hope, and Hype for Psychiatric and Neurologic Conditions

OBJECTIVE: This article presents proven, promising, and potential therapeutic uses for cannabidiol (CBD) in the treatment of psychiatric and neurologic conditions and diseases. It presents popular, but scientifically unproven health and therapeutic claims of CBD supporting the beneficial homeostatic effects of the intrinsic or endogenous cannabinoid system. It includes a review of cannabinoid pharmacology; it compares properties and the legal status of CBD and THC (delta 9-tetrahydrocannabinol) as well as the hemp and marijuana varieties of Cannabis, and it reviews the historic 2018 U.S. Food and Drug Administration approval of Epidiolex, an oral solution of cannabidiol for two rare treatment-resistant childhood epilepsies, as the first Cannabis-derived drug. METHOD: We reviewed literature on cannabidiol, CBD, the endocannabinoid neuropharmacology system, and hemp and marijuana varieties of Cannabis sativa. RESULTS: The proven and promising medical uses and deficiencies of unproven health claims for CBD, legal implications for Cannabis-derived drugs, and comparisons of CBD and THC and hemp and marijuana are summarized objectively with pertinent references. CONCLUSION: CBD and CBD and THC combinations have potential to provide safe, effective therapy for several psychiatric and neurologic conditions and diseases. However, such achievement will require a uniform standard of CBD purity and strength, and corroboration from adequately large and rigorously controlled clinical research studies.

The cloning and characterization of the cannabinoid type 1 receptor

The cloning and characterization of the first cannabinoid receptor (now known as the cannabinoid type 1 (CB1) receptor) by Matsuda et al. in the landmark paper discussed in this chapter was a seminal discovery in 1990. While the analgesic properties of marijuana had been known for thousands of years, the mechanisms through which marijuana produces analgesia were not understood. The identification and functional characterization of the CB1 receptor led to the discovery of an endogenous cannabinoid system (the endocannabinoid system), which has now been shown to be important not only for acute and chronic pain states, but also for a whole host of physiological and pathophysiological disorders.