“The endocannabinoid (eCB) system plays a significant role in the pathophysiology of depression. The potential participation of this system in the mechanism of action of antidepressants has been highlighted in recent years. The aim of this study was to investigate the expression of cannabinoid (CB) receptors using Western blot and CB1 receptor density using autoradiography after acute or chronic administration of antidepressant drugs [imipramine (IMI, 15mg/kg), escitalopram (ESC, 10mg/kg) and tianeptine (TIA, 10mg/kg)]. Antidepressants given chronically elevated CB1 receptor density in the cortical structures and hippocampal areas, while a decrease of CB1 receptor density was observed in the striatum after IMI and ESC treatment. The CB1 receptor expression decreases in the dorsal striatum after chronic administration of IMI and ESC or the receptor rise in the hippocampus after chronic ESC and TIA treatment were confirmed using Western blot analyses. An increase in the CB2 receptor expression was observed in the cortical structures and hippocampus after chronic administration of ESC and TIA, while a decrease in this expression was noted in the striatum and cerebellum after chronic IMI treatment. Our results provide clear evidence that the antidepressant exposures provoke some modulations within the eCB system through CB receptors.” https://www.ncbi.nlm.nih.gov/pubmed/28866072 http://www.sciencedirect.com/science/article/pii/S0161813X17301717]]>
Category Archives: Endocannabinoid System
CB1 Receptors Signaling in the Brain: Extracting Specificity from Ubiquity.
“Endocannabinoids (eCBs) are amongst the most ubiquitous signaling molecules in the nervous system. Over the past few decades, observations based on a large volume of work, first examining the pharmacological effects of exogenous cannabinoids, and then the physiological functions of eCBs, have directly challenged long-held and dogmatic views about communication, plasticity and behavior in the Central Nervous System (CNS). The eCBs and their cognate cannabinoid receptors exhibit a number of unique properties that distinguish them from the widely studied classical amino acid transmitters, neuropeptides and catecholamines. Although we now have a loose set of mechanistic rules based on experimental findings, new studies continue to reveal that our understanding of the endocannabinoid system (ECS) is continuously evolving and challenging long-held conventions. Here, we will briefly summarize findings on the current canonical view of the ‘endocannabinoid system’ and will address novel aspects that reveal how a nearly ubiquitous system can determine highly specific functions in the brain. In particular, we will focus on findings that push for an expansion of our ideas around long-held beliefs about eCB signaling that, whilst clearly true, may be contributing to an oversimplified perspective on how cannabinoid signaling at the microscopic level impacts behavior at the macroscopic level.” https://www.ncbi.nlm.nih.gov/pubmed/28862250 https://www.nature.com/npp/journal/vaop/naam/abs/npp2017206a.html]]>
Explorative Placebo-Controlled Double-Blind Intervention Study with Low Doses of Inhaled Δ9-Tetrahydrocannabinol and Cannabidiol Reveals No Effect on Sweet Taste Intensity Perception and Liking in Humans.
“Introduction: The endocannabinoid system (ECS) plays an important role in food reward. For example, in humans, liking of palatable foods is assumed to be modulated by endocannabinoid activity. Studies in rodents suggest that the ECS also plays a role in sweet taste intensity perception, but it is unknown to what extent this can be extrapolated to humans. Therefore, this study aimed at elucidating whether Δ9-tetrahydrocannabinol (THC) or cannabidiol (CBD) affects sweet taste intensity perception and liking in humans, potentially resulting in alterations in food preferences.
Results: Inhalation of the Cannabis preparations did not affect sweet taste intensity perception and liking, ranking order, or ad libitum consumption of the favorite drink. In addition, food preferences were not influenced by the interventions. Reported fullness was lower, whereas desire to eat was higher throughout the THC compared to the CBD condition.
Conclusions: These results suggest that administration of Cannabis preparations at the low doses tested does not affect sweet taste intensity perception and liking, nor does it influence food preferences in humans.”
https://www.ncbi.nlm.nih.gov/pubmed/28861511
http://online.liebertpub.com/doi/10.1089/can.2017.0018
Affinity and Efficacy Studies of Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and Two.
“Introduction: Cannabis biosynthesizes Δ9-tetrahydrocannabinolic acid (THCA-A), which decarboxylates into Δ9-tetrahydrocannabinol (THC). There is growing interest in the therapeutic use of THCA-A, but its clinical application may be hampered by instability. THCA-A lacks cannabimimetic effects; we hypothesize that it has little binding affinity at cannabinoid receptor 1 (CB1).
Results: The THCA-A reagent contained 2% THC. THCA-A displayed small but measurable binding at both hCB1 and hCB2, equating to approximate Ki values of 3.1μM and 12.5μM, respectively. THC showed 62-fold greater affinity at hCB1 and 125-fold greater affinity at hCB2. In efficacy tests, THCA-A (10μM) slightly inhibited forskolin-stimulated cAMP at hCB1, suggestive of weak agonist activity, and no measurable efficacy at hCB2.
Discussion: The presence of THC in our THCA-A certified standard agrees with decarboxylation kinetics (literature reviewed herein), which indicate contamination with THC is nearly unavoidable. THCA-A binding at 10μM approximated THC binding at 200nM. We therefore suspect some of our THCA-A binding curve was artifact-from its inevitable decarboxylation into THC-and the binding affinity of THCA-A is even weaker than our estimated values. We conclude that THCA-A has little affinity or efficacy at CB1 or CB2.
“Patients with endometriosis often suffer from diffuse and poorly localized severe pain. The current pain management strategies include medical and hormonal therapy, as well as surgery. Medical management of pain is often insufficient and is associated with high rate of recurrence. Better pain management is therefore of urgent need.
Methods: Among the various candidates, the endocannabinoid system (ECS) has recently emerged as a relevant pharmacological target for the management of endometriosis-related pain. A computerized literature search was performed to identify relevant studies combining the keywords “endometriosis,” “endocannabinoid,” “
“An agonist that acts through a single receptor can activate numerous signaling pathways. Recent studies have suggested that different ligands can differentially activate these pathways by stabilizing a limited range of receptor conformations, which in turn preferentially drive different downstream signaling cascades. This concept, termed “biased signaling” represents an exciting therapeutic opportunity to target specific pathways that elicit only desired effects, while avoiding undesired effects mediated by different signaling cascades. The 
“Acute kidney injury (AKI) is associated with a significantly increased risk of morbidity and mortality. Ischemia-reperfusion injury (IRI) is a major cause of AKI. In this study, we investigated the role of the endocannabinoid (EC) system in renal IRI using a well-established mouse model.
Results: Renal IRI was associated with significantly increased serum BUN and creatinine, increased tubular damage score, increased expression of renal markers of inflammation and oxidative stress and elevated renal 2-AG content. Pretreatment with JZL184 was associated with a significant increase in renal 2-AG content and there was also improved serum BUN, creatinine and tubular damage score. However, renal expression of inflammation and oxidative stress markers remained unchanged.
Conclusions: This is the first report documenting that renal IRI is associated with an increase in kidney 2-AG content. Further enhancement of 2-AG levels using JZL184 improved indices of renal function and histology, but did not lower renal expression of markers of inflammation and oxidative stress. Further studies are needed to determine the mechanisms responsible for the effects observed and the potential value of 2-AG as a therapeutic target in renal IRI.”