Endocannabinoids

Czech version

Authors: Suchopár J. ¹; Laštůvka Z. ²; Mašková S. ²; Alblová M. ²; Pařízek A. ²
Authors‘ workplace: DrugAgency, a. s., Praha ¹; Gynekologicko-porodnická klinika 1. LF UK a VFN v Praze ²
Published in: Ceska Gynekol 2021; 86(6): 414-420
Category: Review Article
doi: https://doi.org/10.48095/cccg2021414

Overview

Objective: Overview of current knowledge in the field of the endocannabinoid system with emphasis on the relationships between endocannabinoids and exocannabinoids. The endocannabinoid system consists of cannabinoid receptors 1 and 2, ligands of these receptors, especially two „classical“ endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoyl-glycerol. Transport systems that ensure the entry of endocannabinoids into cells, where they are degraded by fatty acid amide hydrolase or monoacylglycerol lipase. The endocannabinoid system is a signaling pathway for the regulation of a number of physiological or pathological conditions. So far, it is one of the less explored ways of regulation, as evidenced by the recent explosive increase in the number of published works. Dysregulation of endocannabinoid systems is a possible cause of many diseases. It can occur both in the genetic polymorphism of its individual components, but also in therapy with certain drugs or natural substances, typically cannabinoids. Due to the wide overlap of the regulation of physiological functions by the endocannabinoid system, a considerable number of drugs are being developed, the aim of which is to correct the dysregulation of the endocannabinoid system. Conclusion: The endocannabinoid system is one of the most important regulatory systems with a very broad intervention in physiological and pathological conditions. The resulting specific regulations intersect the interplay of many enzymes involved in the production and degradation of endocannabinoids, transport systems involved in the entry of endocannabinoids into cells, cannabinoid receptors and exogenous cannabinoids, or natural substances acting at various sites in the endocannabinoid system. Knowledge in this area can contribute to improving health care and increasing the safety of its provision.

Keywords:

Cannabinoids – Endocannabinoids – anandamide – 2-arachidoyl glycerol – cannabinoid receptor – fatty acid binding proteins – fatty acid amide hydrolases – lipase for monoacylglycerols

Sources

1. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol 2006; 147 (Suppl 1): S163–S171. doi: 10.1038/sj.bjp.0706406.

2. Rodríguez de Fonseca F, Del Arco I, Bermudez-Silva FJ et al. The endocannabinoid system: physiology and pharmacology. Alcohol Alcohol 2005; 40 (1): 2–14. doi: 10.1093/alcalc/ agh110.

3. Maia J, Fonseca BM, Teixeira N et al. The fundamental role of the endocannabinoid system in endometrium and placenta: implications in pathophysiological aspects of uterine and pregnancy disorders. Hum Reprod Update 2020; 26 (4): 586–602. doi: 10.1093/humupd/dmaa 005.

4. Kozakiewicz ML, Grotegut CA, Howlett AC. Endocannabinoid system in pregnancy maintenance and labor: a mini-review. Front Endocrinol (Lausanne) 2021; 12: 699951. doi: 10.3389/ fendo.2021.699951.

5. Matsuda LA, Lolait SJ, Brownstein MJ et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990; 346 (6284): 561–564. doi: 10.1038/346561a0.

6. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993; 365 (6441): 61–65. doi: 10.1038/365061a0.

7. Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol 2008; 20 (Suppl 1): 10–14. doi: 10.1111/j.1365- 2826.2008.01671.x.

8. Devane W, Hanus L, Breuer A et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258 (5090): 1946–1949. doi: 10.1126/science.1470919.

9. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006; 58 (3): 389–462. doi: 10.1124/pr.58.3.2.

10. Okamoto Y, Morishita J, Tsuboi K et al. Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 2004; 279 (7): 5298–5305. doi: 10.1074/jbc.M306642200.

11. Yoshida T, Fukaya M, Uchigashima M et al. Localization of diacylglycerol lipase-alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor. J Neurosci 2006; 26 (18): 4740–4751. doi: 10.1523/jneurosci.0054-06.2006.

12. Fowler CJ. Anandamide uptake explained? Trends Pharmacol Sci 2012; 33 (4): 181–185. doi: 10.1016/j.tips.2012.01.001.

13. Jóźwiak-Bebenista M, Nowak JZ. Paracetamol: mechanism of action, applications and safety concern. Acta Pol Pharm 2014; 71 (1): 11–23.

14. Elmes MW, Kaczocha M, Berger WT et al. Fatty acid-binding proteins (FABPs) are intracellular carriers for Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem 2015; 290 (14): 8711–8721. doi: 10.1074/jbc.M114.618447.

15. Di Marzo V, Maccarrone M. FAAH and anandamide: is 2-AG really the odd one out? Trends Pharmacol Sci 2008; 29 (5): 229–233. doi: 10.1016/j.tips.2008.03.001.

16. Sun YX, Tsuboi K, Zhao LY et al. Involvement of N-acylethanolamine-hydrolyzing acid amidase in the degradation of anandamide and other N-acylethanolamines in macrophages. Biochim Biophys Acta 2005; 1736 (3): 211–220. doi: 10.1016/j.bbalip.2005.08.010.

17. Urquhart P, Nicolaou A, Woodward DF. Endocannabinoids and their oxygenation by cyclo-oxygenases, lipoxygenases and other oxygenases. Biochim Biophys Acta 2015; 1851 (4): 366–376. doi: 10.1016/j.bbalip.2014.12. 015.

18. Savinainen JR, Saario SM, Laitinen JT. The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors. Acta Physiol (Oxf) 2012; 204 (2): 267–276. doi: 10.1111/j.1748- 1716.2011.02280.x.

19. Tripathi RK. A perspective review on fatty acid amide hydrolase (FAAH) inhibitors as potential therapeutic agents. Eur J Med Chem 2020; 188: 111953. doi: 10.1016/j.ejmech.2019.111 953.

20. Li GL, Winter H, Arends R et al. Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects. Br J Clin Pharmacol 2012; 73 (5): 706–716. doi: 10.1111/ j.1365-2125.2011.04137.x.

21. D‘Souza DC, Cortes-Briones J, Creatura G et al. Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial. Lancet Psychiatry 2019; 6 (1): 35–45. doi: 10.1016/s2215-0366 (18) 30 427-9.

22. Rocha JF, Santos A, Gama H et al. Safety, tolerability, and pharmacokinetics of FAAH inhibitor BIA 10-2474: a double-blind, randomized, placebo-controlled study in healthy volunteers. Clin Pharmacol Ther 2021. doi: 10.1002/cpt. 2290.

23. Sipe JC, Chiang K, Gerber AL et al. A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc Natl Acad Sci U S A 2002; 99 (12): 8394–8399. doi: 10.1073/pnas.082235799.

24. Ney LJ, Matthews A, Hsu CK et al. Cannabinoid polymorphisms interact with plasma endocannabinoid levels to predict fear extinction learning. Depress Anxiety 2021; 38 (10): 1087–1099. doi: 10.1002/da.23170.

25. Doris JM, Millar SA, Idris I et al. Genetic polymorphisms of the endocannabinoid system in obesity and diabetes. Diabetes Obes Metab 2019; 21 (2): 382–387. doi: 10.1111/dom.13 504.

26. Bioque M, Mas S, Costanzo MC et al. Gene-environment interaction between an endocannabinoid system genetic polymorphism and cannabis use in first episode of psychosis. Eur Neuropsychopharmacol 2019; 29 (6): 786–794. doi: 10.1016/j.euroneuro.2019.04. 005.

27. Ahmadalipour A, Mehdizadeh Fanid L, Zeinalzadeh N et al. The first evidence of an association between a polymorphism in the endocannabinoid-degrading enzyme FAAH (FAAH rs2295633) with attention deficit hyperactivity disorder. Genomics 2020; 112 (2): 1330–1334. doi: 10.1016/j.ygeno.2019.07.024.

28. Cisar JS, Weber OD, Clapper JR et al. Identification of ABX-1431, a selective inhibitor of monoacylglycerol lipase and clinical candidate for treatment of neurological disorders. J Med Chem 2018; 61 (20): 9062–9084. doi: 10.1021/acs.jmedchem.8b00951.

29. Qin H, Ruan ZH. The role of monoacylglycerol lipase (MAGL) in the cancer progress. Cell Biochem Biophys 2014; 70 (1): 33–36. doi: 10.1007/s12013-014-9899-2.

30. Li X, Gao S, Li W et al. Effect of monoacylglycerol lipase on the tumor growth in endometrial cancer. J Obstet Gynaecol Res 2019; 45 (10): 2043–2054. doi: 10.1111/jog.14070.

31. Bononi G, Poli G, Rizzolio F et al. An updated patent review of monoacylglycerol lipase (MAGL) inhibitors (2018-present). Expert Opin Ther Pat 2021; 31 (2): 153–168. doi: 10.1080/13543776.2021.1841166.

32. Carey CE, Agrawal A, Zhang B et al. Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: evidence from an endocannabinoid system-level analysis. J Abnorm Psychol 2015; 124 (4): 860–877. doi: 10.1037/abn0000079.

33. Elkrief L, Spinney S, Vosberg DE et al. Endocannabinoid gene × gene interaction association to alcohol use disorder in two adolescent cohorts. Front Psychiatry 2021; 12: 645746. doi: 10.3389/fpsyt.2021.645746.

34. Domschke K, Dannlowski U, Ohrmann P et al. Cannabinoid receptor 1 (CNR1) gene: impact on antidepressant treatment response and emotion processing in major depression. Eur Neuropsychopharmacol 2008; 18 (10): 751–759. doi: 10.1016/j.euroneuro.2008.05. 003.

35. Sadeghian M, Rahmani S, Mansoori A. G1359A variant of the cannabinoid receptor gene (rs1049353) and obesity-related traits and related endophenotypes: a meta-analysis. Ann Nutr Metab 2018; 73 (1): 76–85. doi: 10.1159/000490668.

36. Buchmann AF, Hohm E, Witt SH et al. Role of CNR1 polymorphisms in moderating the effects of psychosocial adversity on impulsivity in adolescents. J Neural Transm (Vienna) 2015; 122 (3): 455–463. doi: 10.1007/s00702-014- 1266-3.

37. Qin H, Zeng J, Chen H et al. Can your DNA influence your bet-placing? The impact of cannabinoid receptor 1 gene on gambling tasks. Front Hum Neurosci 2018; 12: 458. doi: 10.3389/ fnhum.2018.00458.

38. Bienertova-Vasku J, Bienert P, Dostalova Z et al. A common variation in the cannabinoid 1 receptor (CNR1) gene is associated with pre-eclampsia in the Central European population. Eur J Obstet Gynecol Reprod Biol 2011; 155 (1): 19–22. doi: 10.1016/j.ejogrb.2010.11. 004.

39. Peiró AM, García-Gutiérrez MS, Planelles B et al. Association of cannabinoid receptor genes (CNR1 and CNR2) polymorphisms and panic disorder. Anxiety Stress Coping 2020; 33 (3): 256–265. doi: 10.1080/10615806.2020.1732 358.

40. Ezzat DA, Hammam AA, El-Malah WM et al. Role of cannabinoid CB2 receptor gene (CNR2) polymorphism in children with immune thrombocytopenic purpura in beni-suef governorate in Egypt. Egypt J Immunol 2017; 24 (1): 57–66.

41. Tahamtan A, Rezaiy S, Samadizadeh S et al. Cannabinoid CB2 receptor functional variation (Q63R) is associated with multiple sclerosis in Iranian subjects. J Mol Neurosci 2020; 70 (1): 26–31. doi: 10.1007/s12031-019-01395-9.

42. Touriño C, Oveisi F, Lockney J et al. FAAH deficiency promotes energy storage and enhances the motivation for food. Int J Obes (Lond) 2010; 34 (3): 557–568. doi: 10.1038/ijo.2009.262.

43. Huang WJ, Chen WW, Zhang X. Endocannabinoid system: role in depression, reward and pain control (Review). Mol Med Rep 2016; 14 (4): 2899–2903. doi: 10.3892/mmr.2016.5585.

44. Di Marzo V, Piscitelli F. The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics 2015; 12 (4): 692–698. doi: 10.1007/s13311-015-0374-6.

45. Schlosburg JE, Radanova L, Di Marzo V et al. Evaluation of the endogenous cannabinoid system in mediating the behavioral effects of dipyrone (metamizol) in mice. Behav Pharmacol 2012; 23 (7): 722–726. doi: 10.1097/FBP.0b013e3283584794.

46. Hayes AW. Commentary on BIA 10-2474. Regul Toxicol Pharmacol 2020; 111: 104541. doi: 10.1016/j.yrtph.2019.104541.