“The endogenous cannabinoid system has been characterized in some female reproductive organs but little is known about the expression and localization pattern of cannabinoid-degrading enzymes in relation to the CB1 cannabinoid receptor in human oocytes. In this study, we focus on the investigation of the presence and differential distribution of fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in relation to CB1 during the maturation of human oocytes. We used a total of 290 human oocytes not suitable for in vitro fertilization/intracytoplasmic sperm injection (ICSI): germinal-vesicle (GV) and metaphase-I (MI) stages and metaphase-II (MII) oocytes that had not developed into an embryo after ICSI.Cannabinoid-degrading enzymes and the cannabinoid CB1 receptor were present in human oocytes. Specifically, FAAH was detected in the periphery of the oocyte from the GV to MI stage and co-localized with CB1. Later, by the MII stage, FAAH was spread within the oocyte, whereas MGLL immunostaining was homogeneous across the oocyte at all stages of maturation and only overlapped with CB1 at the GV stage. This coordinated redistribution of cannabinoid system proteins suggests a role for this system in the maturation of the female gamete.”
Tag Archives: cannabinoid receptors
Cannabinoid receptors are involved in the protective effect of a novel curcumin derivative C66 against CCl4-induced liver fibrosis.
“Liver fibrosis is one of the major causes of morbidity and mortality worldwide and lacks efficient therapy. Recent studies suggest the curcumin protects liver from fibrosis. However, curcumin itself is in low bioavailable concentration when administered orally, and the protective mechanism remains poorly understood. The current study aimed to investigate whether a more stable derivative of curcumin, C66, protects against CCl4-inudced liver fibrosis and examine the underlying mechanism involving cannabinoid receptor (CB receptor). At a dose lower than curcumin itself, C66 displayed a superior anti-fibrotic effect. C66 significantly reduced collagen deposition, pro-inflammatory cytokine expression, and liver enzyme activities. Mechanistic study revealed that C66 treatment decreased CCl4-induced cannabinoid receptor 1 (CB1 receptor) expression and increased cannabinoidreceptor 2 (CB2 receptor) expression, along with an inhibition of JNK/NF-κB-mediated inflammatory signaling. In conclusion, this curcumin derivative attenuates liver fibrosis likely involving a CB/JNK/NF-κB-mediated pathway.”
Role of cannabinoids in gastrointestinal mucosal defense and inflammation.
“Modulating the activity of the endocannabinoid system influences various gastrointestinal physiological and pathophysiological processes, and cannabinoid receptors as well as regulatory enzymes responsible for the synthesis or degradation of endocannabinoids represent potential targets to reduce the development of gastrointestinal mucosal lesions, hemorrhage and inflammation.
Direct activation of CB1 receptors by plant-derived, endogenous or synthetic cannabinoids effectively reduces both gastric acid secretion and gastric motor activity, and decreases the formation of gastric mucosal lesions induced by stress, pylorus ligation, nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol, partly by peripheral, partly by central mechanisms.
Similarly, indirect activation of cannabinoid receptors through elevation of endocannabinoid levels by globally acting or peripherally restricted inhibitors of their metabolizing enzymes (FAAH, MAGL) or by inhibitors of their cellular uptake reduced the gastric mucosal lesions induced by NSAIDs in a CB1 receptor-dependent fashion.
Dual inhibition of FAAH and cyclooxygenase induced protection against both NSAID-induced gastrointestinal damage and intestinal inflammation.
Moreover, in intestinal inflammation direct or indirect activation of CB1 and CB2 receptors exerts also multiple beneficial effects.
Namely, activation of both CB receptors was shown to ameliorate intestinal inflammation in various murine colitis models, to decrease visceral hypersensitivity and abdominal pain, as well as to reduce colitis-associated hypermotility and diarrhea.
In addition, CB1 receptors suppress secretory processes and also modulate intestinal epithelial barrier functions. Thus, experimental data suggest that the endocannabinoid system represents a promising target in the treatment of inflammatory bowel diseases, and this assumption is also confirmed by preliminary clinical studies.”
A Single Intrathecal or Intraperitoneal Injection of CB2 Receptor Agonist Attenuates Bone Cancer Pain and Induces a Time-Dependent Modification of GRK2.
“The objective of this study was to explore the potential role of G-protein-coupled receptor kinase 2 (GRK2) in the progression of cannabinoid 2 receptor (CB2) agonist-induced analgesic effects of bone cancer pain.
The results affirmed CB2 receptor agonists might serve as new treatment targets for bone cancer pain.
Moreover, spinal GRK2 was an important regulator of CB2 receptor agonist-analgesia pathway.”
Cannabinoid CB2 receptors are involved in the regulation of fibrogenesis during skin wound repair in mice.
“Studies have shown that cannabinoid CB2 receptors are involved in wound repair, however, its physiological roles in fibrogenesis remain to be elucidated.
In the present study, the capacity of cannabinoid CB2 receptors in the regulation of skin fibrogenesis during skin wound healing was investigated.
These results indicated that cannabinoid CB2 receptors modulate fibrogenesis and the TGF‑β/Smad profibrotic signaling pathway during skin wound repair in the mouse.”
Study the Effect of Endocannabinoid System on Rat Behavior in Elevated Plus-Maze.
“Previous studies have shown that cannabinoidergic system is involved in anxiety.
The aim of this study is to evaluate the effect of pharmacological stimulation or blocking of CB1 receptors and inhibition of endocannabinoid degradation in anxiety like behavior in elevated plus-maze (EPM) test in rat.
It is concluded that activation of cannabinoid receptor exert anxiolytic effect while blocking of cannabinoid receptor resulted in anxiety behavior. The locomotor activity was not significantly changed by cannabinoid system.
It is suggested that potentiation of cannabinoid system may be therapeutic strategy for the anxiety behavior.”
Plant-derived, synthetic and endogenous cannabinoids as neuroprotective agents. Non-psychoactive cannabinoids, ‘entourage’ compounds and inhibitors of N-acyl ethanolamine breakdown as therapeutic strategies to avoid pyschotropic effects.
“There is good evidence that plant-derived and synthetic cannabinoids possess neuroprotective properties.
These compounds, as a result of effects upon CB(1) cannabinoid receptors, reduce the release of glutamate, and in addition reduce the influx of calcium following NMDA receptor activation.
The major obstacle to the therapeutic utilization of such compounds are their psychotropic effects, which are also brought about by actions on CB(1) receptors. However, synthesis of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol, which also have neuroprotective properties, are increased under conditions of severe inflammation and ischemia, raising the possibility that compounds that prevent their metabolism may be of therapeutic utility without having the drawback of producing psychotropic effects.
In this review, the evidence indicating neuroprotective actions of plant-derived, synthetic and endogenous cannabinoids is presented. In addition, the pharmacological properties of endogenous anandamide-related compounds that are not active upon cannabinoid receptors, but which are also produced during conditions of severe inflammation and ischemia and may contribute to a neuroprotective action are reviewed.”
Stimulation of cannabinoid CB1 receptors prevents nerve-mediated airway hyperreactivity in NGF-induced inflammation in mouse airways.
“In the present study, we tested the hypothesis that cannabinoids have both acute and chronic modulatory effects on nerve-mediated contractions in NGF-induced airway inflammation.
This study shows that stimulation of cannabinoid CB1 receptors modifies the increase of neuronal activity and density in NGF-induced airway inflammation and directly inhibits cholinergic contractions in the airways by a presynaptic mechanism.
These findings indicate a protective role of CB1 receptors in airway inflammation.”
Endocannabinoid system in the brain…and elsewhere.
“The endocannabinoid system is a complex system with endogenous ligands, synthesis and transport processes, specific receptors (CB1 and CB2) and intracellular degrading enzymes.
It is widely distributed in the central nervous system, but also in peripheral organs.
In the brain, endocannabinoids and CB1 receptors are almost ubiquitous and play a role in synaptic plasticity: they modulate, through an inhibitory retrograde action, the release of classical neurotransmitters such as amines, acetylcholine or amino acids.
They may exert a neuroprotective effect, but are also involved in appetite and alcohol/drug dependence.
At the periphery, they are present (and overexpressed in case of abdominal obesity) in various organs involved in energy control and metabolic regulation.
Furthermore, CB2 receptors are also present in the brain, although less numerous than CB1 receptors.
They could attenuate pain and also be neuroprotective.
Selective agonists, antagonists and inverse agonists of CB1 and CB2 receptors are currently developed and open new interesting therapeutic perspectives.”
The endocannabinoid system: novel pathway for cardiometabolic Risk-factor reduction.
“Although rimonabant has been approved for use in several countries, the Food and Drug Administration has expressed concern about the potential for adverse neurologic and psychiatric effects, considering the widespread distribution of CB1 receptors in the brain. While more research is clearly needed, the clinical evidence shows that CB1-receptor blockade with rimonabant improves multiple cardiovascular and metabolic variables, including body weight and waist circumference, HDL-C, triglycerides, and glucose metabolism. Furthermore, these effects, which are probably mediated by both peripheral and central actions in the ECS, appear to be greater than the improvements that would be expected from weight loss alone. There are multiple ongoing and planned studies with rimonabant as well as several other CB-receptor blockers (e.g., taranabant, CP-945,598). While diet and exercise are the cornerstones of cardiometabolic risk-factor reduction, improved pharmacotherapies are urgently needed. The ECS has provided us with new insights and a promising new avenue for the management of obesity and its associated cardiometabolic risk factors.”