Cannabinoid receptor type 1

The cannabinoid receptor type 1, often abbreviated to CB₁, is a G protein-coupled cannabinoid receptor that is found in the brain and is activated by the psychoactive drug cannabis and its active compound THC and by a group of endocannabinoid neurotransmitters including anandamide.

Expression

The CB₁ receptor is encoded by the gene or "CNR1".cite web | title = Entrez Gene: CNR1 cannabinoid receptor 1 (brain)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1268| accessdate = ] Two transcript variants encoding different isoforms have been described for this gene.cite web | title = Entrez Gene: CNR1 cannabinoid receptor 1 (brain)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1268| accessdate = ]

Brain

CB₁ receptors are thought to be the most widely expressed G protein-coupled receptors in the brain. This is key to endocannabinoid-mediated depolarization-induced suppression of inhibition, a very common form of short-term plasticity in which the depolarization of a single neuron induces a reduction in GABA-mediated neurotransmission. Endocannabinoids released from the depolarized neuron bind to CB₁ receptors in the pre-synaptic neuron and cause a reduction in GABA release. Varying levels of CB₁ expression can be detected in the olfactory bulb, cortical regions (neocortex, pyriform cortex, hippocampus, and amygdala), several parts of basal ganglia, thalamic and hypothalamic nuclei and other subcortical regions ("e.g." the septal region), cerebellar cortex, and brainstem nuclei ("e.g." the periaqueductal gray).cite journal | author = Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R | title = The emerging role of the endocannabinoid system in endocrine regulation and energy balance | journal = Endocr. Rev. | volume = 27 | issue = 1 | pages = 73–100 | year = 2006 | pmid = 16306385 | doi = 10.1210/er.2005-0009 | issn = ]

Other

CB₁ is expressed on several cell types of the pituitary gland, in the thyroid gland, and most likely in the adrenal gland. CB₁ is also expressed in several cells relating to metabolism, such as fat cells, muscle cells, liver cells (and also in the endothelial cells, Kupffer cells and stellate cells of the liver), and in the digestive tract. It is also expressed in the lungs and the kidney.

CB₁ is present on Leydig cells and human sperms. In females, it is present in the ovaries, oviducts myometrium, decidua and placenta. It is probably important also for the embryo.

Neuroimaging

The inverse agonist MK-9470 makes it possible to produce "in vivo" images of the distribution of CB₁ receptors in the human brain with positron emission tomography.cite journal | author = Burns HD, Van Laere K, Sanabria-Bohórquez S, Hamill TG, Bormans G, Eng WS, Gibson R, Ryan C, Connolly B, Patel S, Krause S, Vanko A, Van Hecken A, Dupont P, De Lepeleire I, Rothenberg P, Stoch SA, Cote J, Hagmann WK, Jewell JP, Lin LS, Liu P, Goulet MT, Gottesdiener K, Wagner JA, de Hoon J, Mortelmans L, Fong TM, Hargreaves RJ | title = [18F] MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 23 | pages = 9800–5 | year = 2007 | pmid = 17535893 | doi = 10.1073/pnas.0703472104 | issn = ]

Function

Liver

In the liver, activation of the CB₁ receptor is known to increase de novo lipogenesis,cite journal | author = Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L, Kunos G | title = Endocannabinoid activation at hepatic CB₁ receptors stimulates fatty acid synthesis and contributes to diet-induced obesity | journal = J. Clin. Invest. | volume = 115 | issue = 5 | pages = 1298–305 | year = 2005 | pmid = 15864349 | doi = 10.1172/JCI200523057 | issn = ] Activation of presynaptic CB₁ receptors is also known to inhibit sympathetic innervation of blood vessels and contributes to the suppression of the neurogenic vasopressor response in septic shock.cite journal | author = Godlewski G, Malinowska B, Schlicker E | title = Presynaptic cannabinoid CB₁ receptors are involved in the inhibition of the neurogenic vasopressor response during septic shock in pithed rats | journal = Br. J. Pharmacol. | volume = 142 | issue = 4 | pages = 701–8 | year = 2004 | pmid = 15159284 | doi = 10.1038/sj.bjp.0705839 | issn = ]

Gastrointestinal activity

Inhibition of gastrointestinal activity has been observed after administration of Δ⁹-THC, or of anandamide. This effect has been assumed to be CB₁-mediated since the specific CB₁ antagonist SR 141716A (Rimonabant) blocks the effect. Another report, however, suggests that inhibition of intestinal motility may also have a CB₂-mediated component.cite journal | author = Mathison R, Ho W, Pittman QJ, Davison JS, Sharkey KA | title = Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats | journal = Br. J. Pharmacol. | volume = 142 | issue = 8 | pages = 1247–54 | year = 2004 | pmid = 15249429 | doi = 10.1038/sj.bjp.0705889 | issn = ]

Cardiovascular activity

Cannabinoids are well known for their cardiovascular activity. Activation of peripheral CB1 receptors contributes to hemorrhagic and endotoxin-induced hypotension. Anandamide and 2-AG, produced by macrophages and platelets respectively, may mediate this effect.

Pain

Anandamide attenuates the early phase or the late phase of pain behavior produced by formalin-induced chemical damage. This effect is produced by interaction with CB₁ (or CB₁-like) receptors, located on peripheral endings of sensory neurons involved in pain transmission. Palmitylethanolamide, which like anandamide is present in the skin, also exhibits peripheral antinociceptive activity during the late phase of pain behavior. Palmitylethanolamide, however does not bind to either CB₁ or CB₂. Its analgetic activity is blocked by the specific CB₂ antagonist SR 144528, though not by the specific CB₁ antagonist SR 141716A. Hence a CB₂-like receptor was postulated.

Use of antagonists

CB₁ selective antagonists are used for weight reduction and smoking cessation (see Rimonabant). Activation of CB₁ provides neuroprotection after brain injury.cite journal | author = Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E | title = An endogenous cannabinoid (2-AG) is neuroprotective after brain injury | journal = Nature | volume = 413 | issue = 6855 | pages = 527–31 | year = 2001 | pmid = 11586361 | doi = 10.1038/35097089 | issn = ]

Mechanism

Cannabinoid receptors are activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body as cannabis or a related synthetic compound. They are activated in a dose-dependent, stereoselective and pertussis toxin-sensitive manner.

After the receptor is engaged, multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly activated the G protein G_i, which inhibits the enzyme adenylate cyclase (and thereby the production of the second messenger molecule cyclic AMP), and positively influenced inwardly rectifying potassium channels (=Kir or IRK).cite journal | author = Demuth DG, Molleman A | title = Cannabinoid signalling | journal = Life Sci. | volume = 78 | issue = 6 | pages = 549–63 | year = 2006 | pmid = 16109430 | doi = 10.1016/j.lfs.2005.05.055 | issn = ] However, a much more complex picture has appeared in different cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun and many more

Separation between the therapeutically undesirable psychotropic effects, and the clinically desirable ones however, has not been reported with agonists that bind to cannabinoid receptors. THC, as well as the two major endogenous compounds identified so far that bind to the cannabinoid receptors (anandamide and 2-arachidonylglycerol) produce most of their effects by binding to both the CB₁ and CB₂ cannabinoid receptors.Fact|date=January 2008 PBB_Summary
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See also

* Cannabinoid receptor

References

Further reading

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