Endocannabinoid system

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The endocannabinoid system (abbr. For endogenous cannabinoid system ) is a part of the nervous system and includes the cannabinoid - receptors CB 1 and CB 2 with their natural ligands and the downstream intracellular signal transduction after ligand binding in vertebrates .

history

It was named after the active ingredients of the cannabis plant , the cannabinoids , which led to the discovery of this system. The discovery of these specific receptors inevitably led to the realization that the body's own ligands (endocannabinoids) must also exist for these receptors.

In 1992 Devane and colleagues were able to isolate and subsequently synthesize the first substance that binds to the CB 1 receptor from pig brains : a condensation product of arachidonic acid and ethanolamine , N -arachidonylethanolamide (AEA), which is often called anandamide (based on the Sanskrit word for "bliss": Ananda ). In 1993 γ-linolenoylethanolamide and docosatetraenoylethanolamide followed , in 1997 2-arachidonylglycerol (2-AG), in 2001 2-arachidonylglyceryl ether (“noladin ether”) and in 2002 O -arachidonylethanolamide ( virodhamine ).

Cannabinoid receptors

Cannabinoids activate so-called cannabinoid receptors. To date, two cannabinoid receptors have been described, both of which belong to the class of G-protein-coupled receptors . Both cannabinoid receptors modulate different ion channels. Furthermore, various signaling pathways within the cell are influenced by cannabinoid receptors:

  1. The cannabinoid receptor 1 (or CB 1 for short ) is mainly found in nerve cells. It is most common in the cerebellum , basal ganglia and hippocampus . But it can also be found in the peripheral nervous system (e.g. in the intestine ).
  2. The cannabinoid receptor 2 (or CB 2 for short ), on the other hand, is mainly found on cells of the immune system and on cells that are involved in bone formation ( osteoblasts ) and breakdown ( osteoclasts ).

Furthermore, it is assumed that the G-protein-coupled receptors GPR18 , GPR119 and GPR55 are also cannabinoid receptors in the endocannabinoid system.

Agonists and antagonists

The cannabinoid system can be influenced pharmacologically. Cannabinoids have an agonistic effect , see Dronabinol . The CB 1 blocker rimonabant , which was available in Germany from September 2006 to 2008 for the treatment of abdominal obesity (since it has since been taken off the market), has an antagonistic effect and would also have gained medical importance as an adjuvant drug for smoking cessation from nicotine or alcohol if it had not been withdrawn from the market due to its psychological side effects.

A large number of agonists and antagonists are also used in research. This makes it possible to selectively block or activate one of the receptor types without affecting the other.

N -Palmitoylethanolamine (PEA) is another substance with an endocannabinoid-like effect thatoccursin the stratum granulosum of the skin and, among other things. a. has an antioxidant protective effect against UVB radiation.

2-arachidonylglycerol and arachidonylethanolamide are derivatives of arachidonic acid and are formed by enzymes in lipid metabolism .

Functional importance

Little is known about the functional importance of the endocannabinoid system. The distribution of the receptors suggests a number of possible functions. It is assumed that the CB 2 receptor plays an important role in the regulation or modulation of the immune system.

Since the brain regions in which the CB 1 receptor is predominantly found play an important role in memory ( hippocampus and cerebellum ) and movement regulation ( basal ganglia and cerebellum), it is reasonable to assume that endocannabinoids influence learning and movement processes.

Endogenous cannabinoids are released into the synaptic gap by postsynaptic nerve cells and have a retrograde (feedback) effect on the presynaptic neuron. This creates an inhibition of the transmitter action at the affected synapse. This effect is mediated through three different mechanisms:

  1. Decrease in the activity of presynaptic calcium channels ,
  2. Increase in the activity of postsynaptic calcium channels and
  3. Inhibition of adenylyl cyclase and thereby reducing the activity of protein kinase A .

Cannabinoid-dependent forms of synaptic plasticity have already been identified in the cerebellum in particular . These are called depolarization-induced suppression of excitation (DSE) and depolarization-induced suppression of inhibition (DSI). Both occur at the synapses of the Purkinje cells , DSE at the excitatory and DSI at the inhibitory synapses.
However, a receptor-independent effect of endocannabinoids has recently also been found on Purkinje cells. Endocannabinoids therefore directly inhibit the P-type calcium channels in these cells.
The endogenous activation of the CB 1 receptor is necessary for the correct adaptation of the eyelid closing reflex . This form of associative learning takes place exclusively in the cerebellum.

Current research shows that the CB 1 receptor may be necessary for erasing negative memories. Endocannabinoids could therefore play an important role in anxiety disorders . A study at the Max Planck Institute for Psychiatry on knockout mice without CB 1 receptors showed that unlearning negative experiences was much more difficult.

Other physiological processes that involve the endocannabinoid system include: a. Pain conditions , sleep induction , appetite and motility control , temperature control, neuroprotection and cancer .

Studies with partly contradicting results were carried out in patients with

literature

Web links

Individual evidence

  1. ↑ L. Console-Bram, J. Marcu, ME Abood: Cannabinoid receptors: nomenclature and pharmacological principles. In: Progress in Neuro-Psychopharmacology & Biological Psychiatry . Volume 38, Number 1, July 2012, pp. 4-15, ISSN  1878-4216 . doi: 10.1016 / j.pnpbp.2012.02.009 , PMID 22421596 , PMC 3378782 (free full text).
  2. ↑ GPR119 G protein-coupled receptor 119 (human). In: ncbi.nlm.nih.gov. Retrieved December 18, 2015 .
  3. ↑ GPR18 G protein-coupled receptor 18 (human). In: ncbi.nlm.nih.gov. Retrieved December 18, 2015 .
  4. ↑ GPR55 G protein-coupled receptor 55 (human). In: ncbi.nlm.nih.gov. Retrieved December 18, 2015 .
  5. ^ AJ Brown: Novel cannabinoid receptors. In: British journal of pharmacology. Volume 152, Number 5, November 2007, pp. 567-575, doi : 10.1038 / sj.bjp.0707481 , PMID 17906678 , PMC 2190013 (free full text) (review).
  6. ↑ D. McHugh, SS Hu, N. Rimmerman, A. Juknat, Z. Vogel, JM Walker, HB Bradshaw: N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor. In: BMC neuroscience. Volume 11, 2010, p. 44, doi : 10.1186 / 1471-2202-11-44 , PMID 20346144 , PMC 2865488 (free full text).
  7. ↑ PE Castillo, TJ Younts, AE Chavez, Y. Hashimotodani: Endocannabinoid signaling and synaptic function. In: Neuron. Volume 76, Number 1, October 2012, pp. 70-81, ISSN  1097-4199 . doi: 10.1016 / j.neuron.2012.09.020 , PMID 23040807 , PMC 3517813 (free full text).
  8. ^ S. Ruehle, AA Rey, F. Remmers, B. Lutz: The endocannabinoid system in anxiety, fear memory and habituation. In: Journal of Psychopharmacology . Volume 26, Number 1, January 2012, pp. 23-39, ISSN  1461-7285 . doi: 10.1177 / 0269881111408958 , PMID 21768162 , PMC 3267552 (free full text).
  9. ↑ Cannabis receptor extinguishes fear - ORF ON Science. In: sciencev1.orf.at. Retrieved January 5, 2016 .
  10. ↑ Giovanni Marsicano, Carsten T. Wotjak, Shahnaz C. Azad, Tiziana Bisogno, Gerhard Rammes, Maria Grazia Cascio, Heike Hermann, Jianrong Tang, Clementine Hofmann, Walter Zieglgänsberger, Vincenzo Di Marzo, Beat Lutz: The endogenous cannabinoid system controls extinction of aversive memories. In: Nature. 418, 2002, p. 530, doi : 10.1038 / nature00839 .
  11. ^ R. Schicho, M. Storr: A potential role for GPR55 in gastrointestinal functions. In: Current Opinion in Pharmacology . Volume 12, Number 6, December 2012, pp. 653-658, ISSN  1471-4973 . doi: 10.1016 / j.coph.2012.09.009 , PMID 23063456 , PMC 3660623 (free full text).
  12. ↑ DJ Hermanson, LJ Marnett: Cannabinoids, endocannabinoids, and cancer. In: Cancer Metastasis Reviews . Volume 30, Number 3-4, December 2011, pp. 599-612, ISSN  1573-7233 . doi: 10.1007 / s10555-011-9318-8 , PMID 22038019 , PMC 3366283 (free full text).