“Extensive evidence indicates that endocannabinoids modulate cognitive processes in animal models and human subjects. However, the results of endocannabinoid system manipulations on cognition have been contradictory. As for anxiety behavior, a duality has indeed emerged with regard to cannabinoid effects on memory for emotional experiences. Here we summarize findings describing cannabinoid effects on memory acquisition, consolidation, retrieval and extinction. Additionally, we review findings showing how the endocannabinoid system modulates memory function differentially, depending on the level of stress and arousal associated with the experimental context. Based on the evidence reviewed here, we propose that the endocannabinoid system is an emotional buffer that moderates the effects of environmental context and stress on cognitive processes.”
Category Archives: Endocannabinoid System
Role of the endocannabinoid system in brain functions relevant for schizophrenia: An overview of human challenge studies with cannabis or ∆9-tetrahydrocannabinol (THC).
“Accumulating evidence suggests involvement of the endocannabinoid system in the pathophysiology of schizophrenia, which signifies a potential application for this system in the treatment of this disorder.
…similarities in brain function between intoxicated healthy volunteers and schizophrenia patients provide an argument for a role of the endocannabinoid system in symptoms of schizophrenia, and further emphasise this system as a potential novel target for treatment of these symptoms.”
Cannabinoids, eating behaviour, and energy homeostasis.
“Soon after the discovery of cannabis by western societies, its psychotropic effects overshadowed its medical benefits. However, investigation into the molecular action of the main constituents of cannabis has led to the discovery of an intercellular signalling system, called the endocannabinoid system (ECS).
The ECS comprises a set of molecular components, including enzymes, signalling lipids and G-protein coupled receptors, which has an outstanding role in modulating eating behaviour and energy homeostasis. Interestingly, evidence has shown that the ECS is present at the central and peripheral nervous system, modulating the function of the hypothalamus, the brain reward system and the brainstem, and coordinating the crosstalk between these brain structures and peripheral organs.
Indeed, the ECS is present and functional in metabolically relevant peripheral tissues, directly modulating their physiology. In the context of a global obesity pandemic, these discoveries are highly suggestive in order to design novel pharmaceutical tools to fight obesity and related morbidities.
In fact, a cannabinoid-based first generation of drugs was developed and marketed. Their failure, due to central side-effects, is leading to a second generation of these drugs unable to cross the blood-brain barrier, as well as other ECS-focused strategies that are still in the pipeline. In the next few years we will hopefully know whether such an important player in energy homeostasis can be successfully targeted without significantly affecting other vital processes related to mood and sense of well-being.”
A potential role for GPR55 in the regulation of energy homeostasis.
“G protein-coupled receptor 55 (GPR55) is a putative cannabinoid receptor that is expressed in several tissues involved in regulating energy homeostasis, including the hypothalamus, gastrointestinal tract, pancreas, liver, white adipose and skeletal muscle.
GPR55 has been shown to have a role in cancer and gastrointestinal inflammation, as well as in obesity and type 2 diabetes mellitus (T2DM).
Despite this, the (patho)physiological role of GPR55 in cell dysfunction is still poorly understood, largely because of the limited identification of downstream signalling targets.
Nonetheless, research has suggested that GPR55 modulation would be a useful pharmacological target in metabolically active tissues to improve treatment of diseases such as obesity and T2DM.
Further research is essential to gain a better understanding of the role that this receptor might have in these and other pathophysiological conditions.”
Endocannabinoids: a unique opportunity to develop multitarget analgesics.
“After 4 millennia of more or less documented history of cannabis use, the identification of cannabinoids, and of Δ(9)-tetrahydrocannabinol in particular, occurred only during the early 1960s, and the cloning of cannabinoid CB1 and CB2 receptors, as well as the discovery of endocannabinoids and their metabolic enzymes, in the 1990s.
Despite this initial relatively slow progress of cannabinoid research, the turn of the century marked an incredible acceleration in discoveries on the “endocannabinoid signaling system,” its role in physiological and pathological conditions, and pain in particular, its pharmacological targeting with selective agonists, antagonists, and inhibitors of metabolism, and its previously unsuspected complexity.
The way researchers look at this system has thus rapidly evolved towards the idea of the “endocannabinoidome,” that is, a complex system including also several endocannabinoid-like mediators and their often redundant metabolic enzymes and “promiscuous” molecular targets.
These peculiar complications of endocannabinoid signaling have not discouraged efforts aiming at its pharmacological manipulation, which, nevertheless, now seems to require the development of multitarget drugs, or the re-visitation of naturally occurring compounds with more than one mechanism of action.
In fact, these molecules, as compared to “magic bullets,” seem to offer the advantage of modulating the “endocannabinoidome” in a safer and more therapeutically efficacious way.
This approach has provided so far promising preclinical results potentially useful for the future efficacious and safe treatment of chronic pain and inflammation.”
The Endocannabinoid System and Sex Steroid Hormone-Dependent Cancers.
“The “endocannabinoid system (ECS)” comprises the endocannabinoids, the enzymes that regulate their synthesis and degradation, the prototypicalcannabinoid receptors (CB1 and CB2), some noncannabinoid receptors, and an, as yet, uncharacterised transport system.
Recent evidence suggests that both cannabinoid receptors are present in sex steroid hormone-dependent cancer tissues and potentially play an important role in those malignancies.
Sex steroid hormones regulate the endocannabinoid system and the endocannabinoids prevent tumour development through putative protective mechanisms that prevent cell growth and migration, suggesting an important role for endocannabinoids in the regulation of sex hormone-dependent tumours and metastasis.
Here, the role of the endocannabinoid system in sex steroid hormone-dependent cancers is described and the potential for novel therapies assessed.”
Involvement of cannabinoid receptors in peripheral and spinal morphine analgesia.
“The interactions between the cannabinoid and opioid systems for pain modulation are reciprocal. However, the role and the importance of the cannabinoid system in the antinociceptive effects of opioids remain uncertain. We studied these interactions with the goal of highlighting the involvement of the cannabinoid system in morphine-induced analgesia.
In both phases of the formalin test, intra paw and intrathecal morphine produced similar antinociceptive effects in C57BL/6, cannabinoid type 1 and type 2 receptor wildtype (respectively cnr1WT and cnr2WT) mice. In cnr1 and cnr2 knockout (KO) mice, at the dose used the antinociceptive effect of intra paw morphine in the inflammatory phase of the formalin test was decreased by 87% and 76%, respectively. Similarly, the antinociceptive effect of 0.1 μg spinal morphine in the inflammatory phase was abolished in cnr1KO mice and decreased by 90% in cnr2KO mice. Interestingly, the antinociceptive effect of morphine in the acute phase of the formalin test was only reduced in cnr1KO mice. Notably, systemic morphine administration produced similar analgesia in all genotypes, in both the formalin and the hot water immersion tail flick tests.
Because the pattern of expression of the mu opioid receptor (MOP), its binding properties and its G protein coupling remained unchanged across genotypes, it is unlikely that the loss of morphine analgesia in the cnr1KO and cnr2KO mice is the consequence of MOP malfunction or downregulation due to the absence of its heterodimerization with either the CB1 or the CB2 receptors, at least at the level of the spinal cord.”
Endocannabinoid signalling in neuronal migration.
“The endocannabinoid (eCB) system consists of several endogenous lipids, their target CB1 and CB2 receptors and enzymes responsible for their synthesis and degradation. The most abundant eCB in the central nervous system (CNS), 2-arachidonoyl glycerol (2-AG), triggers a broad range of signalling events by acting on CB1, the most abundant G protein-coupled receptor in the CNS. The eCB system regulates many physiological processes including neurogenesis, axon guidance and synaptic plasticity. Recent studies have highlighted an additional important role for eCB signalling in neuronal migration, which is crucial to achieve the complex architecture and efficient wiring of the CNS. Indeed, eCB signalling controls migration both pre- and post-natally, regulating interneuron positioning in the developing cortex and hippocampus and the polarized motility of stem cell-derived neuroblasts. While these effects may contribute to cognitive deficits associated with cannabis consumption, they also provide potential opportunities for endogenous stem cell-based neuroregenerative strategies.”
The promise and dilemma of cannabinoid therapy: lessons from animal studies of bone disease.
“The endocannabinoid system plays an important role in numerous physiological processes and represents a potential drug target for diseases ranging from brain disorders to cancer…
In the aging skeleton, CB1 deficiency causes accelerated osteoporosis characterized mainly by a significant reduction in bone formation coupled to enhanced adipocyte accumulation in the bone marrow.
A similar acceleration of bone loss was also reported in aging CB2-deficient mice but found to be associated with enhanced bone turnover.
This perspective describes the role of cannabinoid ligands and their receptors in bone metabolism and highlights the promise and dilemma of therapeutic exploitation of the endocannabinoid system for treatment of bone disorders.”
The cytokine and endocannabinoid systems are co-regulated by NF-κB p65/RelA in cell culture and transgenic mouse models of Huntington’s disease and in striatal tissue from Huntington’s disease patients.
“Transcriptional dysregulation is a major pathological feature of Huntington’s disease (HD). The goal of this study was to understand how p65/RelA co-regulated genes, specifically those of the cytokine and endocannabinoid systems, were affected in HD. p65/RelA levels were lower in human HD tissue and R6/2 HD mice, as were the levels of the type 1 cannabinoid receptor (CB1), IL-1β, IL-8, CCL5, GM-CSF, MIP-1β, and TNFα, all of which may be regulated by p65/RelA. Activation of p65/RelA restored CB1 and CCL5 expression in STHdh cell models of HD. Therefore, p65/RelA activation may normalize the expression of some genes in HD.”