“The endocannabinoid signaling plays a critical role in mediating rewarding effects to morphine. The relative stability for the expression and reinstatement of morphine conditioned place preference (CPP) suggests the involvement of differential neuroadaptations in learned associations between environmental cues and morphine. Changes in gene expression in hippocampus through the endogenous cannabinoid system (eCB) may accompany and mediate the development of such neuroadaptations to repeated morphine stimulation. To test this possibility, we systematically compared the expression of eCB-related genes in the dorsal hippocampus following the expression, extinction, and reinstatement of morphine CPP using quantitative RT-PCR analyses. These results suggest that differential regulation of the synthesis and/or degradation of the eCB system contribute to the expression and reinstatement of morphine CPP.” https://www.ncbi.nlm.nih.gov/pubmed/28192193]]>
Category Archives: Endocannabinoid System
Endocannabinoid-dependent protection against kainic acid-induced long-term alteration of brain oscillations in guinea pigs.
“Changes in rhythmic activity can serve as early biomarkers of pathological alterations, but it remains unclear how different types of rhythmic activity are altered during neurodegenerative processes. Glutamatergic neurotoxicity, evoked by kainic acid (KA), causes hyperexcitation and acute seizures that result in delayed brain damage. We employed wide frequency range (0.1-300 Hz) local field potential recordings in guinea pigs to study the oscillatory activity of the hippocampus, entorhinal cortex, medial septum, and amygdala in healthy animals for three months after KA introduction. To clarify whether the activation of endocannabinoid (eCB) system can influence toxic KA action, AM404, an eCB reuptake inhibitor, and URB597, an inhibitor of fatty acid amide hydrolase, were applied. Our results demonstrate the protective potential of the eCB system during excitotoxic influences.” https://www.ncbi.nlm.nih.gov/pubmed/28192082]]>
Cannabinoids activate monoaminergic signaling to modulate key C. elegans behaviors.
“Cannabis or marijuana, a popular recreational drug, alters sensory perception and exerts a range of potential medicinal benefits. The present study demonstrates that the endogenous cannabinoid receptor agonists, 2-arachidonoylglycerol (2-AG) and anandamide (AEA) activate a canonical cannabinoid receptor in C. elegans and also modulate monoaminergic signaling at multiple levels. 2-AG or AEA inhibit nociception and feeding through a pathway requiring the cannabinoid-like receptor, NPR-19. 2-AG or AEA activate NPR-19 directly and cannabinoid-dependent inhibition can be rescued in npr-19 null animals by the expression of a human cannabinoid receptor, CB1, highlighting the orthology of the receptors. Cannabinoids also modulate nociception and locomotion through an NPR-19-independent pathway requiring an α2A-adrenergic-like octopamine receptor, OCTR-1, and a 5-HT1A-like receptor, SER-4, that involves a complex interaction among cannabinoid, octopaminergic and serotonergic signaling. 2-AG activates OCTR-1 directly. In contrast, 2-AG does not activate SER-4 directly, but appears to enhance SER-4-dependent serotonergic signaling by increasing endogenous 5-HT. This study defines a conserved cannabinoid signaling system in C. elegans, demonstrates the cannabinoid-dependent activation of monoaminergic signaling and highlights the advantages of studying cannabinoid signaling in a genetically-tractable whole animal model. SIGNIFICANCE STATEMENTCannabis sativa causes euphoria and exerts a wide range of medicinal benefits. For years, cannabinoids have been studied at the cellular level using tissue explants with conflicting results. To better understand cannabinoid signaling, we have used the C. elegans model to examine the effects of cannabinoids on behavior. The present study demonstrates that mammalian cannabinoid receptor ligands activate a conserved cannabinoid signaling system in C. elegans and also modulate monoaminergic signaling, potentially impacting an array of disorders, including anxiety and depression. This study highlights the potential role of cannabinoids in modulating monoaminergic signaling, and the advantages of studying cannabinoid signaling in a genetically-tractable, whole-animal model.” https://www.ncbi.nlm.nih.gov/pubmed/28188220]]>
Cannabinoid Receptors in Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance.
“Cannabinoid receptors are fundamentally involved in all aspects of intestinal physiology, such as motility, secretion, and epithelial barrier function. They are part of a broader entity, the so-called endocannabinoid system which also includes their endocannabinoid ligands and the ligands’ synthesizing/degrading enzymes.
The system has a strong impact on the pathophysiology of the gastrointestinal tract and is believed to maintain homeostasis in the gut by controlling hypercontractility and by promoting regeneration after injury.
For instance, genetic knockout of cannabinoid receptor 1 leads to inflammation and cancer of the intestines. Derivatives of Δ9-tetrahydrocannabinol, such as nabilone and dronabinol, activate cannabinoid receptors and have been introduced into the clinic to treat chemotherapy-induced emesis and loss of appetite; however, they may cause many psychotropic side effects.
New drugs that interfere with endocannabinoid degradation to raise endocannabinoid levels circumvent this obstacle and could be used in the future to treat emesis, intestinal inflammation, and functional disorders associated with visceral hyperalgesia.”
https://www.ncbi.nlm.nih.gov/pubmed/28161834
Activation of cannabinoid receptors elicits antidepressant-like effects in a mouse model of social isolation stress.
“Social isolation stress (SIS) paradigm is a chronic stress procedure able to induce profound behavioral and neurochemical changes in rodents and evokes depressive and anxiety-like behaviors. Recent studies demonstrated that the cannabinoid system plays a key role in behavioral abnormalities such as depression through different pathways; however, there is no evidence showing a relation between SIS and the cannabinoid system. This study investigated the role of the cannabinoid system in depressive-like behavior and anxiety-like behavior of IC animals. Our findings suggest that the cannabinoid system is involved in depressive-like behaviors induced by SIS. We showed that activation of cannabinoid receptors (type 1 and 2) could mitigate depression-like behavior induced by SIS in a mouse model.” https://www.ncbi.nlm.nih.gov/pubmed/28161196]]>
A selective CB2R agonist (JWH133) restores neuronal circuit after Germinal Matrix Hemorrhage in the preterm via CX3CR1+ microglia.
“Microglia play dual roles after germinal matrix hemorrhage, and the neurotrophic phenotype maybe neuroprotective.
We raise the hypothesis that a cannabinoid receptor2 agonist (JWH133) accelerates the CX3CR1+ microglia secreting neurotrophic factors and restores damaged neuronal circuit.
Overall, this study provides evidence that JWH133 promoted a neurotrophic phenotype of microglia (CX3CR1+ microglia), beyond merely alleviating microglial proliferation and inflammation.
Moreover, JWH133 restored impaired neuronal circuit, which represent a novel therapeutic strategy following GMH in clinic.”
https://www.ncbi.nlm.nih.gov/pubmed/28153531]]>
Tumor-promoting effects of cannabinoid receptor type 1 in human melanoma cells.
“The role of endocannabinoid system in melanoma development and progression is actually not fully understood. This study was aimed at clarifying whether cannabinoid-type 1 (CB1) receptor may function as tumor-promoting or -suppressing signal in human cutaneous melanoma. Findings of this study suggest that CB1 receptor might function as tumor-promoting signal in human cutaneous melanoma.” https://www.ncbi.nlm.nih.gov/pubmed/28131817
“Antitumor effects of THC.” http://www.ncbi.nlm.nih.gov/pubmed/11097557
“Cannabinoids (CB) like ∆9-tetrahydrocannabinol (THC) can induce cancer cell apoptosis and inhibit angiogenesis. Our results confirm the value of exogenous cannabinoids for the treatment of melanoma” http://www.ncbi.nlm.nih.gov/pubmed/25921771
The involvement of cannabinoids and mTOR in the reconsolidation of an emotional memory in the hippocampal-amygdala-insular circuit.
“Memory reconsolidation is the process in which reactivated long-term memory becomes transiently sensitive to amnesic agents. We evaluated the ability of post reactivation administration of the mTOR inhibitor rapamycin, separately and in combination with the cannabinoid CB1/2 receptor agonist WIN55,212-2 (WIN), given systemically or specifically into the hippocampal CA1 area, basolateral amygdala (BLA) or insular cortex (IC), to reduce inhibitory avoidance fear in rats. Taken together, the results suggest that rapamycin or a combined treatment that involves blocking mTOR and activating cannabinoids may be a promising pharmacological approach for the attenuation of reactivated emotional memories, and thus, it could represent a potential treatment strategy for disorders associated with traumatic memories.” https://www.ncbi.nlm.nih.gov/pubmed/28131675]]>
Antihyperalgesic effect of CB1 receptor activation involves the modulation of P2X3 receptor in the primary afferent neuron.
“Cannabinoid system is a potential target for pain control. Cannabinoid receptor 1 (CB1) activation play a role in the analgesic effect of cannabinoids once it is expressed in primary afferent neurons. This study investigates whether the anti-hyperalgesic effect of CB1receptor activation involves P2×3 receptor in primary afferent neurons. Our data suggest that the analgesic effect of CB1 receptor activation is mediated by a negative modulation of the P2×3 receptor in the primary afferent neurons.” https://www.ncbi.nlm.nih.gov/pubmed/28131783]]>
Endocannabinoid Signaling and the Hypothalamic-Pituitary-Adrenal Axis.
“The elucidation of Δ9-tetrahydrocannabinol as the active principal of Cannabis sativa in 1963 initiated a fruitful half-century of scientific discovery, culminating in the identification of the endocannabinoid signaling system, a previously unknown neuromodulatory system. A primary function of the endocannabinoid signaling system is to maintain or recover homeostasis following psychological and physiological threats. We provide a brief introduction to the endocannabinoid signaling system and its role in synaptic plasticity. The majority of the article is devoted to a summary of current knowledge regarding the role of endocannabinoid signaling as both a regulator of endocrine responses to stress and as an effector of glucocorticoid and corticotrophin-releasing hormone signaling in the brain. We summarize data demonstrating that cannabinoid receptor 1 (CB1R) signaling can both inhibit and potentiate the activation of the hypothalamic-pituitary-adrenal axis by stress. We present a hypothesis that the inhibitory arm has high endocannabinoid tone and also serves to enhance recovery to baseline following stress, while the potentiating arm is not tonically active but can be activated by exogenous agonists. We discuss recent findings that corticotropin-releasing hormone in the amygdala enables hypothalamic-pituitary-adrenal axis activation via an increase in the catabolism of the endocannabinoid N-arachidonylethanolamine. We review data supporting the hypotheses that CB1R activation is required for many glucocorticoid effects, particularly feedback inhibition of hypothalamic-pituitary-adrenal axis activation, and that glucocorticoids mobilize the endocannabinoid 2-arachidonoylglycerol. These features of endocannabinoid signaling make it a tantalizing therapeutic target for treatment of stress-related disorders but to date, this promise is largely unrealized.” https://www.ncbi.nlm.nih.gov/pubmed/28134998]]>