Skip to main content

Endocannabinoid System Components: Overview and Tissue Distribution

  • Chapter
  • First Online:
Recent Advances in Cannabinoid Physiology and Pathology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1162))

Abstract

Marijuana/cannabinoid research has been transformed into mainstream science during the last half-century. Evidence based research and remarkable biotechnological advances demonstrate that phytocannabinoids and endocannabinoid (eCBs) acting on cannabinoid receptors (CBRs) regulate various aspects of human physiological, behavioral, immunological and metabolic functions. The distribution and function of the components of the endocannabinoid system (ECS) in the central nervous system (CNS) and immune processes have garnished significant research focus with major milestones. With these advances in biotechnology, rapid extension of the ECS research in the periphery has gained momentum. In this chapter, we review the components and tissue distribution of this previously unknown but ubiquitous and complex ECS that is involved in almost all aspects of mammalian physiology and pathology.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 69.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 89.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 119.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

2-AG:

2-arachidonyl glycerol

CBRs:

cannabinoid receptors

CNS:

central nervous system

eCB:

endocannabinoids

ECS:

endocannabinoid system

ENS:

enteric nervous system

ER:

endoplasmic reticulum

GABA:

gamma-aminobutyric acid

GI:

gastrointestinal

mtCBR:

mitochondrial cannabinoid receptor

NAc:

nucleus accumbens

p-CREB:

phosphor-cAMP response element-binding protein

PPARs:

peroxisome proliferator-activated receptors

THC:

tetrahydrocannabinol

TRPV1:

transient receptor potential vanilloid type 1

CNR:

cannabinoid receptor gene

GPCR:

G-protein coupled receptor

References

  1. Mechoulam R, Gaoni Y (1967) Recent advances in the chemistry of hashish. Fortschr Chem Org Naturst 25:175–213

    CAS  PubMed  Google Scholar 

  2. Mechoulam R, Parker L (2013) Towards a better cannabis drug. Br J Pharmacol 170:1361–1364

    Article  Google Scholar 

  3. Uhl GR, Ishiguro H, Onaivi ES, Zhang PW, Akinshola BE, Lin Z et al (2006) Molecular neurobiological methods in marijuana-cannabinoid research. In: Onaivi ES (ed) Methods in molecular medicine: marijuana and cannabinoid research: methods and protocols. Humana Press, Totowa, pp 1–17

    Google Scholar 

  4. O’Brien CP (2006) Preface. In: Onaivi ES, Sugiura T, Di Marzo V (eds) Endocannabinoids: the brain and body’s marijuana and beyond. Taylor and Francis, Boca Raton

    Google Scholar 

  5. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G et al (1992) Isolation and brain structure of a brain constituents that binds to the cannabinoid receptor. Science 258:1946–1949

    Article  CAS  Google Scholar 

  6. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K et al (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid ligand in brain. Biochem Biophys Res Commun 215:89–97

    Article  CAS  Google Scholar 

  7. Onaivi ES, Ishiguro H, Gu S, Liu QR (2012) CNS effects of CB2 cannabinoid receptors: beyond neuro-immuno-cannabinoid activity. J Psychopharmacol 26:92–103

    Article  CAS  Google Scholar 

  8. Di Marzo V, Stella N, Zimmer A (2015) Endocannabinoid signaling and deteriorating brain. Nat Rev Neurosci 16:3042

    Article  Google Scholar 

  9. A report of the National Academies of Sciences, Engineering, Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. The National Academies Press, Washington, DC, 2017

    Google Scholar 

  10. Spiller KJ, Bi GH, He Y, Galaj E, Gardner EL, Xi Z-X (2019) Cannabinoid CB1 and CB2 receptor mechanisms underlie cannabis reward and aversion in rats. Br J Pharmacol 176:1268–1281

    Article  CAS  Google Scholar 

  11. Piotrowska Z, Niezgoda M, Lebkowski W, Filipek A, Domian N, Kasacka I (2018) Sex differences in distribution of cannabinoid receptors (CB1 and CB2), S100A6 and CacyBP/SIP in human aging hearts. Bio Sex Differences. https://doi.org/10.1186/s13293-018-0209-3

  12. Sterin-Borda L, Del Zar CF, Borda E (2005) Differential CB1 and CB2 cannabinoid receptor-ionotropic response of rat isolated atria: endogenous signal transduction pathways. Biochem Pharmacol 69:1705–1713

    Article  CAS  Google Scholar 

  13. Li Q, Guo HC, Maslov LN, Qiao XW, Zhou JJ, Zhang Y (2014) Mitochondrial permeability transition pore plays a role in the cardioprotection of CB2 receptor against ischemia-reperfusion injury. Can J Physiol Pharmacol 92:205–214

    Article  CAS  Google Scholar 

  14. Hebert-Chatelain E, Marsicano G, Desprez T (2017) Cannabinoids and mitochondria. In: Melis M (ed) Endocannabinoids and lipid mediators in brain functions. Springer, Cham, pp 211–235

    Chapter  Google Scholar 

  15. Bénard G, Massa F, Puente N, Lourenço J, Bellocchio L, Soria-Gómez E et al (2012) Mitochondrial CB (1) receptors regulate neuronal energy metabolism. Nat Neurosci 15:558–564

    Article  Google Scholar 

  16. Hebert-Chatelain E, Desprez T, Serrat R, Bellocchio L, Soria-Gomez E, Busquets-Garcia A (2016) A cannabinoid link between mitochondria and memory. Nature 539:555–559

    Article  CAS  Google Scholar 

  17. Brusco A, Tagliaferro P, Saez T, Onaivi ES (2008) Postsynaptic localization of CB2 cannabinoid receptors in the rat hippocampus. Synapse 62:944–949

    Article  CAS  Google Scholar 

  18. Brusco A, Tagliaferro PA, Saez T, Onaivi ES (2008) Ultrastructural localization of neuronal brain CB2 cannabinoid receptors. Ann N Y Acad Sci 1139:450–457

    Article  CAS  Google Scholar 

  19. Ong WY, Mackie K (1999) A light and electron microscopic study of the CB1 cannabinoid receptor in the primate spinal cord. J Neurocytol 28:39–45

    Article  CAS  Google Scholar 

  20. Castaneda JT, Harui A, Roth MD (2017) Regulation of cell surface CB2 receptor during human B cell activation and differentiation. J NeuroImmune Pharmacol 12:544–554

    Article  Google Scholar 

  21. Fede C, Albertin G, Petrelli L, Sfriso MM, Biz C, De Caro R et al (2016) Expression of the endocannabinoid receptors in human fascial tissue. Eur J Histchemistry 60:2643

    CAS  Google Scholar 

  22. Galligan JJ (2009) Cannabinoid signaling in the enteric nervous system. Neurogastroenterol Motil 21:899–902

    Article  CAS  Google Scholar 

  23. Stander S, Schmelz M, Metze D, Luger T, Rukwied R (2005) Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J Dermatol Sci 38:177–188

    Article  Google Scholar 

  24. Maccarrone M, Bab I, Biro T, Cabral GA, Dey SK, Di Marzo V et al (2015) Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 36:277–295

    Article  CAS  Google Scholar 

  25. Toth KF, Adam D, Biro T, Olah A (2019) Cannabinoid signaling in the skin: therapeutic potential of the “C(ut)annabinoid” system. Molecules 24:918. https://doi.org/10.3390/molecules24050918

    Article  CAS  PubMed Central  Google Scholar 

  26. del Rio C, Millan E, Garcia V, Appendino G, DeMessa J, Munoz E (2018) The endocannabinoid system of the skin. A potential approach for treatment of skin disorders. Biochem Pharmacol 157:122–133

    Article  CAS  Google Scholar 

  27. Dustin H, Marks BS, Friedman A (2018) The therapeutic potential of cannabinoids in dermatology. Kin Therapy Lett 23:1–5

    Google Scholar 

  28. Maida V, Corban J (2017) Topical medical cannabis: a new treatment for wound pain – three cases of Pyoderma Gangrenosum. J Pain Symptom Manag 54:732–737

    Article  Google Scholar 

  29. Mounessa JS, Siegel JA, Dunnick CA, Dellavalle RP (2017) The role of cannabinoids in dermatology. J Am Acad Dermatol 77:188–190

    Article  Google Scholar 

  30. Hashim PW, Cohen JL, Pomei DT, Goldenberg G (2017) Topical cannabinoids in dermatology. Cutis 100:50–52

    PubMed  Google Scholar 

  31. Olah A, Biro T (2017) Targeting cutaneous cannabinoid signaling in inflammation – a “HIGH” – way to heal? EBioMedicine 16:3–5

    Article  Google Scholar 

  32. Nassan FL, Arvizu M, Minguez-Alarcon L, Williams PL, Attaman J, Petrozza J et al (2019) Marijuana smoking and markers of testicular function among men from a fertility centre. Hum Reprod 34:715–723

    Article  Google Scholar 

  33. Van Waes V, Beverley J, Siman H, Tseng KY, Steiner H (2012) CB1 cannabinoid receptor expression in the striatum: association with corticostriatal circuits and developmental regulation. Front Pharmacol 3:21. https://doi.org/10.3389/fphar.2012.00021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Farquhar-Smith WP, Egertová M, Bradbury EJ, McMahon SB, Rice AS, Elphick MR (2000) Cannabinoid CB1 receptor expression in rat spinal cord. Mol Cell Neurosci 15:510–521

    Article  CAS  Google Scholar 

  35. Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11:4213 4225

    Article  Google Scholar 

  36. Hurley MJ, Mash DC, Jenner P (2003) Expression of cannabinoid CB1 receptor mRNA in basal ganglia of normal and parkinsonian human brain. J Neural Transm 110:1279–1288

    Article  CAS  Google Scholar 

  37. Gonzalez-Mariscal I, Krzysik-Walker SM, Doyle ME, Liu QR, Cimbro R, Calyo SSC et al (2016) Human CB1 receptor isoforms, present in hepatocytes and B-cells, are involved in regulating metabolism. Scientific Reports 6:33302

    Article  CAS  Google Scholar 

  38. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Taglaiferro PA, Brusco A et al (2006) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 1071:10–23

    Article  CAS  Google Scholar 

  39. Zhang HY, Bi GH, Li X, Li J, Qu H, Zhang SJ et al (2015) Species differences in cannabinoid receptor 2 and receptor responses to cocaine self-administration in mice and rats. Neuropsychopharmacology 40:1037–1051

    Article  CAS  Google Scholar 

  40. Liu QR, Huang NS, Qu H, O’Connell JF, Gonzalez-Mariscal I, Santa-Cruz-Calvo S et al (2018) Identification of novel mouse and rat isoforms and in silco modeling of human CB1R for peripheral cannabinoid therapeutics. Acta Pharmacol Sin 0:1–11. https://doi.org/10.1038/s41401-018-0152-1

    Article  CAS  Google Scholar 

  41. Ortega-Gutierrez S, Lopez-Rodriguez ML (2005) CB1 and CB2 cannabinoid receptor binding studies based on meodelling and mutagenesis approaches. Min-Rev Med Chem 5:651–658

    Article  CAS  Google Scholar 

  42. Onaivi ES (2006) Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB2 receptors in the brain. Neuropsychobiology 54:231–246

    Article  CAS  Google Scholar 

  43. Liu QR, Canseco-Alba A, Zhang HY, Taglaiferro P, Chung M, Dennis E et al (2017) Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference. Sci Rep 7:17410

    Article  Google Scholar 

  44. Onaivi ES, Ishiguro H, Liu QR (2015) Future perspectives: cannabinoid CB2 receptor ligands and their therapeutic potential in mental diseases. In: Fattore L (ed) Cannabinoids in neurological and mental disease, pp 425–444

    Chapter  Google Scholar 

  45. Ndong C, O’Donnell D, Ahmad S, Groblewski T (2011) Cloning and pharmacological characterization of the dog cannabinoid CB2 receptor. Eur J Pharmacol 669:24–31

    Article  CAS  Google Scholar 

  46. Zhang PW, Ishiguro H, Ohtsuki T, Hess J, Carillo F, Walther D et al (2004) Human cannabinoid receptor 1:5 exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Mol Psychiatry 9:916–931

    Article  CAS  Google Scholar 

  47. Sipe JC, Arbour N, Gerber A, Beutler E (2005) Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders. J Leukoc Biol 78:231–238

    Article  CAS  Google Scholar 

  48. Karsak M, Cohen-Solal M, Freudenberg J, Ostertag A, Morieux C, Kornak U et al (2005) Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum Mol Genet 14:3389–3396

    Article  CAS  Google Scholar 

  49. Ishiguro H, Carpio O, Horiuchi Y, Shu A, Higuchi S, Schanz N et al (2010) A nonsynonymous polymorphism in cannabinoid CB2 receptor gene is associated with eating disorders in humans and food intake is modified in mice by its ligands. Synapse 64:92–96

    Article  CAS  Google Scholar 

  50. Ishiguro H, Horiuchi Y, Ishikawa M, Koga M, Imai K, Suzuki Y et al (2010) Brain cannabinoid CB2 receptor in schizophrenia. Biol Psychiatry 67:974–982

    Article  CAS  Google Scholar 

  51. Ishiguro H, Iwasaki S, Teasenfitz L, Higuchi S, Horiuchi Y, Saito T et al (2007) Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans. Pharm J 7:380–385

    CAS  Google Scholar 

  52. Iwasaki S, Ishiguro H, Higuchi S, Onaivi ES, Arinami T (2007) Association study between alcoholism and endocannabinoid metabolic enzyme genes encoding fatty acid amide hydrolase and monglyceride lipase in a Japanese population. Psychat Genet 17:215–220

    Article  Google Scholar 

  53. Onaivi ES, Ishiguro H, Gong J, Patel S, Perchuk A, Meozzi PA et al (2006) Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann N Y Acad Sci 1074:514–536

    Article  CAS  Google Scholar 

  54. Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L et al (2008) Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects. PLoS One 3:e1640

    Article  Google Scholar 

  55. Murphy WJ, Eizirik E, Johnson WE, Zhang YP, Ryder OA, O’Brien SJ (2001) Molecular phylogenetics and the origins of placental mammals. Nature 409:614–814

    Article  CAS  Google Scholar 

  56. Vasileiou I, Fotopoulou G, Matzourani M, Patsouris E, Theocharis S (2013) Evidence for the involvement of cannabinoid receptor’s polymorphisms in the pathophysiology of human diseases. Expert Opin Ther Targets 17:363–377

    Article  CAS  Google Scholar 

  57. Liu QR, Pan CH, Hishimotor A, Li CY, Xi ZX, Llorente-Berzal A et al (2009) Species differences in cannabinoid receptor 2 (CNR2 gene): identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands. Genes Brain Behav:519–530

    Google Scholar 

  58. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K et al (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332

    Article  Google Scholar 

  59. Ghose H (2009) Cannabinoid controversy. The Scientist. Available at: http://www.the-scientist.com/news/display/55969

  60. Atwood BK (2010) Mackie k. CB2: a cannabinoid receptor with an identity crisis. Br J Pharmacol 160:467–479

    Article  CAS  Google Scholar 

  61. Rogers N (2015) Cannabinoid receptor with an ‘identity crisis’ gets a second look. Mat Med 21:966–967

    CAS  Google Scholar 

  62. Stempel AV, Stumpf A, Zhang HY, Ozdogan T, Pannasch U, Theis AK (2016) Cannabinoid type 2 receptors mediate a cell type-specific plasticity in the hippocampus. Neuron 90:795–809

    Article  CAS  Google Scholar 

  63. Onaivi ES, Chaudhuri G, Abaci AS, Parker M, Manier DH, Martin PR (1999) Expression of cannabinoid receptors and their gene transcripts in human blood cells. Prog Neuro-Psychopharmacol Bio Psychiat 23:1063–1077

    Article  CAS  Google Scholar 

  64. Onaivi ES (2010) Endocannabinoid system, pharmacogenomics and response to therapy. Pharmacogenomics 11:907–910

    Article  CAS  Google Scholar 

  65. Laurikainen H, Tuominen L, Tikka M, Merisaari H, Armio RL, Sormunen E et al (2019) Sex difference in brain CB1 receptor availability in man. NeuroImage 184:834–842

    Article  CAS  Google Scholar 

  66. Piotrowska Z, Niezgoda M, Lebkowski W, Filipek A, Domian N, Kasacka I (2018) Sex differences in distribution of cannabinoid receptors (CB1 and CB2), S100A6 and CacyBP/SP in human ageing hearts. Biol Sex Differ 9:50

    Article  Google Scholar 

  67. Schlienz NJ, Budney AJ, Lee DC, Vandrey R (2017) Cannabis withdrawal: a review of neurobiological mechanisms and sex differences. Curr Addict Reports 4:75–81

    Article  Google Scholar 

  68. Rubino T, Realini N, Guidali C, Braida D, Capurro V, Castiglioni C et al (2008) Chronic d9-tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adults: behavioral and biochemical correlates. Neuropsychopharmacology 33:2760

    Article  CAS  Google Scholar 

  69. Farquhar CE, Breivogel CS, Gamage TF, Gay EA, Thomas BF, Craft RM et al (2019) Sex, THC, and hormones: Effects on density and sensitivity of CB1 cannabinoid receptors. Drug Alcohol Depend 194:20–27

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Emmanuel S. Onaivi .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Joshi, N., Onaivi, E.S. (2019). Endocannabinoid System Components: Overview and Tissue Distribution. In: Bukiya, A. (eds) Recent Advances in Cannabinoid Physiology and Pathology. Advances in Experimental Medicine and Biology, vol 1162. Springer, Cham. https://doi.org/10.1007/978-3-030-21737-2_1

Download citation

Publish with us

Policies and ethics