The endocannabinoid system (ECS) is a complex signaling system that is present in most, if not all, mammalian species. It plays a crucial role in maintaining homeostasis by regulating a variety of physiological processes, including metabolic, immune, and reproductive functions.[1-2] The ECS consists of cannabinoid receptors, endogenous ligands known as endocannabinoids, and enzymes responsible for the synthesis and degradation of these ligands.[2-3] The two primary cannabinoid receptors identified are CB1 and CB2, and the major endocannabinoids are anandamide and 2-arachidonoylglycerol (2-AG).[2][4]
The widespread distribution of the ECS components across different mammalian organs and the conservation of key elements of the ECS across species, including rodents and non-human primates, support the notion that all mammals possess an endocannabinoid system.[1-2][5] However, there is evidence of species-specific differences in the expression patterns of ECS components, which may have implications for the translational relevance of preclinical models to human physiology and disease.[1][5]
In summary, the current consensus in the medical literature indicates that the endocannabinoid system is a fundamental and ubiquitous component of mammalian biology, and thus, it is reasonable to conclude that all mammals have an endocannabinoid system.
References
Rosado-Franco JJ, Ellison AL, White CJ, et al.
Physiological Reports. 2024;12(4):e15947. doi:10.14814/phy2.15947.
New Research
The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system have not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were no receptors with identical expression patterns among mice (three males and two females), rats (six females), and rhesus macaques (four males). Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.
2.The Endocannabinoid System in the Adipose Organ.
Jung KM, Lin L, Piomelli D.
Reviews in Endocrine & Metabolic Disorders. 2022;23(1):51-60. doi:10.1007/s11154-020-09623-z.
Top Journal
The endocannabinoid system is found in most, if not all, mammalian organs and is involved in a variety of physiological functions, ranging from the control of synaptic plasticity in the brain to the modulation of smooth muscle motility in the gastrointestinal tract. This signaling complex consists of G protein-coupled cannabinoid receptors, endogenous ligands for those receptors (endocannabinoids) and enzymes/transporters responsible for the formation and deactivation of these ligands. There are two subtypes of cannabinoid receptors, CB and CB, and two major endocannabinoids, arachidonoylethanolamide (anandamide) and 2-arachidonoyl-sn-glycerol (2-AG), which are produced upon demand through cleavage of distinct phospholipid precursors. All molecular components of the endocannabinoid system are represented in the adipose organ, where endocannabinoid signals are thought to regulate critical homeostatic processes, including adipogenesis, lipogenesis and thermogenesis. Importantly, obesity was found to be associated with excess endocannabinoid activity in visceral fat depots, and the therapeutic potential of normalizing such activity by blocking CB receptors has been the focus of substantial preclinical and clinical research. Results have been mixed thus far, mostly owing to the emergence of psychiatric side effects rooted in the protective functions served by brain endocannabinoids in mood and affect regulation. Further studies about the roles played by the endocannabinoid system in the adipose organ will offer new insights into the pathogenesis of obesity and might help identify new ways to leverage this signaling complex for therapeutic benefit.
3.Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives.
Meccariello R.
International Journal of Molecular Sciences. 2020;21(10):E3549. doi:10.3390/ijms21103549. Copyright License: CC BY
The endocannabinoid system (ECS) is a complex signaling system that includes cannabinoid receptors, their endogenous ligands (endocannabinoids), and biosynthetic and hydrolytic enzymes […].
Di Marzo V.
Pharmacological Research. 2009;60(2):77-84. doi:10.1016/j.phrs.2009.02.010.
Highly Relevant
Top Journal
The endocannabinoid signalling system includes: (1) at least two G-protein-coupled receptors, known as the cannabinoid CB(1) and CB(2) receptors and discovered following studies on the mechanism of action of Delta(9)-tetrahydrocannabinol, the major psychoactive principle of the hemp plant Cannabis sativa; (2) the endogenous agonists at these receptors, known as endocannabinoids, of which anandamide and 2-arachidonoylglycerol are the best known; and (3) proteins and enzymes for the regulation of endocannabinoid levels and action at receptors. The endocannabinoid system is quite widespread in mammalian tissues and cells and appears to play a pro-homeostatic role by being activated following transient or chronic perturbation of homeostasis, and by regulating in a local way the levels and action of other chemical signals. Compounds that selectively manipulate the action and levels of endocannabinoids at their targets have been and are being developed, and represent templates for potential new therapeutic drugs.
Rodriguez-Sanchez IP, Guindon J, Ruiz M, et al.
Neurotoxicology and Teratology. 2016 Nov – Dec;58:23-30. doi:10.1016/j.ntt.2016.06.006.
Highly Relevant
Introduction: The consumption of marijuana (exogenous cannabinoid) almost doubled in adults during last decade. Consumption of exogenous cannabinoids interferes with the endogenous cannabinoid (or “endocannabinoid” (eCB)) system (ECS), which comprises N-arachidonylethanolamide (anandamide, AEA), 2-arachidonoyl glycerol (2-AG), endocannabinoid receptors (cannabinoid receptors 1 and 2 (CB1R and CB2R), encoded by CNR1 and CNR2, respectively), and synthesizing/degrading enzymes (FAAH, fatty-acid amide hydrolase; MAGL, monoacylglycerol lipase; DAGL-α, diacylglycerol lipase-alpha). Reports regarding the toxic and therapeutic effects of pharmacological compounds targeting the ECS are sometimes contradictory. This may be caused by the fact that structure of the eCBs varies in the species studied.
Objectives: First: to clone and characterize the cDNAs of selected members of ECS in a non-human primate (baboon, Papio spp.), and second: to compare those cDNA sequences to known human structural variants (single nucleotide polymorphisms and haplotypes).
Materials And Methods: Polymerase chain reaction-amplified gene products from baboon tissues were transformed into Escherichia coli. Amplicon-positive clones were sequenced, and the obtained sequences were conceptually translated into amino-acid sequences using the genetic code.
Results: Among the ECS members, CNR1 was the best conserved gene between humans and baboons. The phenotypes associated with mutations in the untranslated regions of this gene in humans have not been described in baboons. One difference in the structure of CNR2 between humans and baboons was detected in the region with the only known clinically relevant polymorphism in a human receptor. All of the differences in the amino-acid structure of DAGL-α between humans and baboons were located in the hydroxylase domain, close to phosphorylation sites. None of the differences in the amino-acid structure of MAGL observed between baboons and humans were located in the area critical for enzyme function.
Conclusion: The evaluation of the data, obtained in non-human primate model of cannabis-related developmental exposure should take into consideration possible evolutionary-determined species-specific differences in the CB1R expression, CB2R transduction pathway, and FAAH and DAGLα substrate-enzyme interactions.
