“The type-1 cannabinoid receptor (CB1) is the main effector of the endocannabinoid system (ECS), which is involved in most brain and body functions. In this Perspective, we provide evidence indicating that CB1 receptor functions are key determinants of bodily coordinated exostatic processes. First, we will introduce the concepts of endostasis and exostasis as compensation or accumulation for immediate or future energy needs and discuss how exostasis has been necessary for the survival of species during evolution. Then, we will argue how different specific biological functions of the CB1 receptor in the body converge to provide physiological exostatic processes. Finally, we will introduce the concept of proactive evolution-induced diseases (PEIDs), which helps explain the seeming paradox that an evolutionary-selected physiological function can become the cause of epidemic pathological conditions, such as obesity. We propose here a possible unifying theory of CB1 receptor functions that can be tested by future experimental studies.” https://www.ncbi.nlm.nih.gov/pubmed/28334603]]>
Category Archives: Endocannabinoid System
Fatty-acid-binding protein inhibition produces analgesic effects through peripheral and central mechanisms.
“Fatty-acid-binding proteins (FABPs) are intracellular carriers for endocannabinoids, N-acylethanolamines, and related lipids. Previous work indicates that systemically administered FABP5 inhibitors produce analgesia in models of inflammatory pain. It is currently not known whether FABP inhibitors exert their effects through peripheral or central mechanisms. Here, we examined FABP5 distribution in dorsal root ganglia and spinal cord and examined the analgesic effects of peripherally and centrally administered FABP5 inhibitors.
Results: Immunofluorescence revealed robust expression of FABP5 in lumbar dorsal root ganglia. FABP5 was distributed in peptidergic calcitonin gene-related peptide-expressing dorsal root ganglia and non-peptidergic isolectin B4-expressing dorsal root ganglia. In addition, the majority of dorsal root ganglia expressing FABP5 also expressed transient receptor potential vanilloid 1 (TRPV1) and peripherin, a marker of nociceptive fibers. Intraplantar administration of FABP5 inhibitors reduced thermal and mechanical hyperalgesia in the complete Freund’s adjuvant model of chronic inflammatory pain. In contrast to its robust expression in dorsal root ganglia, FABP5 was sparsely distributed in the lumbar spinal cord and intrathecal administration of FABP inhibitor did not confer analgesic effects. Administration of FABP inhibitor via the intracerebroventricular (i.c.v.) route reduced thermal hyperalgesia. Antagonists of peroxisome proliferator-activated receptor alpha blocked the analgesic effects of peripherally and i.c.v. administered FABP inhibitor while antagonism of cannabinoid receptor 1 blocked the effects of peripheral FABP inhibition and a TRPV1 antagonist blocked the effects of i.c.v. administered inhibitor. Although FABP5 and TRPV1 were co-expressed in the periaqueductal gray region of the brain, which is known to modulate pain, knockdown of FABP5 in the periaqueductal gray using adeno-associated viruses and pharmacological FABP5 inhibition did not produce analgesic effects.
Conclusions: This study demonstrates that FABP5 is highly expressed in nociceptive dorsal root ganglia neurons and FABP inhibitors exert peripheral and supraspinal analgesic effects. This indicates that peripherally restricted FABP inhibitors may serve as a new class of analgesic and anti-inflammatory agents.”
https://www.ncbi.nlm.nih.gov/pubmed/28326944
Overactivation of the endocannabinoid system alters the anti-lipolytic action of insulin in mouse adipose tissue.
“Evidence has accumulated that obesity-related metabolic dysregulation is associated with overactivation of the endocannabinoid system (ECS), which involves cannabinoid receptor 1 (CB1R), in peripheral tissues, including adipose tissue (AT). The functional consequences of CB1R activation on AT metabolism remain unclear. Since excess fat mobilization is considered an important primary event contributing to the onset of insulin resistance, we combined in vivo and in vitro experiments to investigate whether activation of ECS could alter the lipolytic rate. For this purpose, the appearance of plasma glycerol was measured in wild-type and CB1R-/- mice after acute anandamide administration or inhibition of endocannabinoid degradation by JZL195. Additional experiments were conducted on rat AT explants to evaluate the direct consequences of ECS activation on glycerol release and signaling pathways. Treatments stimulated glycerol release in mice fasted for 6 h and injected with glucose but not in 24-h fasted mice or in CB1R-/-suggesting that the effect was dependent on plasma insulin levels and mediated by CB1R. We concomitantly observed that Akt cascade activity was decreased, indicating an alteration of the anti-lipolytic action of insulin. Similar results were obtained with tissue explants exposed to anandamide, thus identifying CB1R of AT as a major target. This study indicates the existence of a functional interaction between CB1R and lipolysis regulation in AT. Further investigation is needed to test whether the elevation of ECS tone encountered in obesity is associated with excess fat mobilization contributing to ectopic fat deposition and related metabolic disorders.” https://www.ncbi.nlm.nih.gov/pubmed/28325733]]>
Antidiabetic, antidyslipidemic and toxicity profile of ENV-2: A potent pyrazole derivative against diabetes and related diseases.
“Diabetes is a major health problem and a predisposition factor for further degenerative complications and, therefore, novel therapies are urgently needed. Currently, cannabinoid receptor 1 (CB1 receptor) antagonists have been considered as promissory entities for metabolic disorders treatment. Accordingly, the purpose of this work was the evaluation of the sub-acute antidiabetic, anti-hyperglycemic, antidyslipidemic and toxicological profile of ENV-2, a potent hypoglycemic and antioxidant CB1 receptor antagonist. In this study, ENV-2 showed a pronounced anti-hyperglycemic effect even at a dose of 5mg/kg (P< 0.001) in a glucose tolerance test on normoglycemic rats. Moreover, after administration of ENV-2 (16mg/kg) to diabetic rats, a prominent antidiabetic activity was observed (P< 0.001), which was higher than glibenclamide. Sub-acute treatment (10 days) of ENV-2 resulted in a significant reduction of plasma glucose (P< 0.001). Also, the levels of peripheral lipids were improved; blood triacylglycerols (TG) and cholesterol (CHOL) were diminished (P< 0.001). In addition, it was found that ENV-2 reduced IL-1β and IL-18 mRNA expression in adipose tissue (P< 0.05). Due to the satisfactory outcomes, we were interested in evaluating the toxicity of ENV-2 in both acute and sub-chronic approaches. Regarding the acute administration, the compound resulted to be non-toxic and was grouped in category 5 according to OECD. It was also found that sub-chronic administration did not increase the size of the studied organs, while no structural damage was observed in heart, lung, liver and kidney tissues. Finally, neither AST nor ALT damage hepatic markers were augmented.” https://www.ncbi.nlm.nih.gov/pubmed/28322830]]>
Cannabinoid receptor 1 contributes to sprouted innervation in endometrial ectopic growth through mitogen-activated protein kinase activation.
“The endocannabinoid system regulates neurite outgrowth and neurogenesis during development of the central nervous system. Cannabinoid receptor 1 (CB1R) is expressed in neurons, including the somata and fibers, that innervate the endometrial ectopic cyst in rats. This finding may provide a new therapeutic target for patients with endometriosis.” https://www.ncbi.nlm.nih.gov/pubmed/28322749]]>
2-Arachidonoylglycerol ameliorates inflammatory stress-induced insulin resistance in cardiomyocytes.
“Several studies have linked impaired glucose uptake and insulin resistance (IR) to functional impairment of the heart. Recently, endocannabinoids have been implicated in cardiovascular disease. However, the mechanisms involving endocannabinoid signaling, glucose uptake and IR in cardiomyocytes are understudied. Here, we report the endocannabinoid 2-Arachidonoylglycerol (2-AG) via stimulation of cannabinoid type-1 (CB1) receptor and Ca2+/Calmodulin-dependent protein kinase β (CaMKKβ) activates AMPK leading to increased glucose uptake. Interestingly, we have observed that the mRNA expression of CB1 and CB2 receptors was decreased in diabetic mice, indicating reduced endocannabinoid signaling in diabetic heart. We further establish that TNFα induces IR in cardiomyocytes. Treatment with 2-AG suppresses TNFα-induced pro-inflammatory markers, and improves IR and glucose uptake. Conversely, pharmacological inhibition or knockdown of AMPK attenuates the anti-inflammatory effect and reversal of IR elicited by 2-AG. Additionally, in human embryonic stem cell-derived cardiomyocytes challenged with TNFα or free fatty acid (FFA), we demonstrate that 2-AG improves insulin sensitivity and glucose uptake. In conclusion, 2-AG abates inflammatory responses, increases glucose uptake and overcomes IR in an AMPK-dependent manner in cardiomyocytes.” https://www.ncbi.nlm.nih.gov/pubmed/28320859]]>
Rimonabant, a selective cannabinoid1 receptor antagonist, protects against light-induced retinal degeneration in vitro and in vivo.
“The endocannabinoid system is involved in some neurodegenerative diseases such as Alzheimer’s disease. An endogenous constellation of proteins related to cannabinoid1 receptor signaling, including free fatty acids, diacylglycerol lipase, and N-acylethanolamine-hydrolyzing acid amidase, are localized in the murine retina. Moreover, the expression levels of endogenous agonists of cannabinoid receptors are changed in the vitreous fluid. However, the role of the endocannabinoid system in the retina, particularly in the light-induced photoreceptor degeneration, remains unknown. Therefore, we investigated involvement of the cannabinoid1 receptor in light-induced retinal degeneration using in vitro and in vivo models. Rimonabant suppressed light-induced photoreceptor cell death. Cannabinoid1 receptor expression was upregulated by light exposure. Treatment with rimonabant improved both a- and b-wave amplitudes and the thickness of the outer nuclear layer. These results suggest that the cannabinoid1 receptor is involved in light-induced retinal degeneration and it may represent a therapeutic target in the light-induced photoreceptor degeneration related diseases.” https://www.ncbi.nlm.nih.gov/pubmed/28315677]]>
Hepatic expressions of cannabinoid receptors CB1 and CB2 correlate with the fibrogenesis in patients with chronic hepatitis B.
“The endocannabinoid system is involved in the pathogenesis of liver fibrosis. However, most of the findings come from experiment researches on animal model or clinical trial on chronic hepatitis C. The roles of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) in hepatofibrosis on patients with chronic hepatitis B(CHB) have not been studied universally. This study aimed to explore the relationship between liver fibrosis and expressions of CB1 and CB2 on patients with CHB. The hepatic expressions of CB1 and CB2 play important roles during the progression of fibrosis induced by CHB. Endogenous activation of CB1 receptors in patients with CHB enhances fibrogenesis by direct effect on activated HSCs.” https://www.ncbi.nlm.nih.gov/pubmed/28315398]]>
Cannabis Reduces Opioid Dose in the Treatment of Chronic Non-Cancer Pain
“Cannabinoids block pain responses in virtually every laboratory pain model tested.
In models of acute or physiological pain, cannabinoids are highly effective against thermal, mechanical, and chemical pain, and are comparable to opioids in potency and efficacy.1 In models of chronic pain, cannabinoids exhibit efficacy in the modulation of both inflammatory2 and neuropathic pain.3
Recent reviews describe an endogenous cannabinoid system involved in pain modulation that produces analgesia through the same brainstem circuitry involved in opioid analgesia.1., 4., 5., 6. Although co-administration of Δ-9-tetrahydrocannabinol (THC) with μ opioid agonists can potentiate the antinociceptive effects of each agent, an opioid is not required for cannabinoid analgesia.5., 6. Co-administration of a cannabinoid may lead to a lower opioid requirement. In an N-of-1 trial, oral THC reduced the pain of familial Mediterranean fever such that the use of breakthrough opioid for pain relief decreased significantly.7
Recently, in Canada, the Medical Marijuana Access Program allows patients to apply to Health Canada for access to dried cannabis for medicinal purposes. Although smoked cannabis is not an ideal delivery system, it is efficient and results in plasma concentration curves parallel to those seen after intravenous administration.8 We present three patients who used small doses of smoked marijuana in combination with an opioid.
These cases are consistent with preclinical work demonstrating that cannabinoids exhibit analgesic effects and may potentiate the antinociceptive effects of opioids. These patients were able to decrease the dose of opioid by 60–100% as compared to before the regular use of smoked marijuana. With the introduction of smoked marijuana, each patient reported better pain control.
Unfortunately, the source of smoked marijuana used by patients, and the percentage of THC in it, is unknown. All patients reported previous exposure to cannabis at some time in their lives before the onset of their pain, and the relevance of this experience also is unknown. Standardized measures of pain were not used, and the information presented was based on the patients’ verbal report when they presented for follow-up appointments at the Pain Management Unit. Nonetheless, these cases suggest that further research regarding the role of cannabinoids as analgesics and the combination of cannabinoids with opioids in the control of pain is needed.”
http://www.jpsmjournal.com/article/S0885-3924(03)00142-8/fulltext]]>Cannabis for Pain and Headaches: Primer.
“Marijuana has been used both medicinally and recreationally since ancient times and interest in its compounds for pain relief has increased in recent years. The identification of our own intrinsic, endocannabinoid system has laid the foundation for further research. Synthetic cannabinoids are being developed and synthesized from the marijuana plant such as dronabinol and nabilone. The US Food and Drug Administration approved the use of dronabinol and nabilone for chemotherapy-associated nausea and vomiting and HIV (Human Immunodeficiency Virus) wasting. Nabiximols is a cannabis extract that is approved for the treatment of spasticity and intractable pain in Canada and the UK. Further clinical trials are studying the effect of marijuana extracts for seizure disorders. Phytocannabinoids have been identified as key compounds involved in analgesia and anti-inflammatory effects. Other compounds found in cannabis such as flavonoids and terpenes are also being investigated as to their individual or synergistic effects. This article will review relevant literature regarding medical use of marijuana and cannabinoid pharmaceuticals with an emphasis on pain and headaches.” https://www.ncbi.nlm.nih.gov/pubmed/28281107]]>