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


The CB1 receptor is encoded by the gene or CNR1.[1] Two transcript variants encoding different isoforms have been described for this gene.[1] CNR1 orthologs [2] have been identified in most mammals.


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).[3]


CB1 is expressed on several cell types of the pituitary gland, in the thyroid gland, and most likely in the adrenal gland.[3] 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.[3] 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.[3]


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.[4]



In the liver, activation of the CB1 receptor is known to increase de novo lipogenesis,[5] 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.[6]

Gastrointestinal activityEdit

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.[7]

Cardiovascular activityEdit

Cannabinoids are well known for their cardiovascular activity. Activation of peripheral CB1 receptors contributes to hemorrhagic and endotoxin-induced hypotension.[8] Anandamide and 2-AG, produced by macrophages and platelets respectively, may mediate this effect.[8]


Anandamide attenuates the early phase or the late phase of pain behavior produced by formalin-induced chemical damage.[citation needed] This effect is produced by interaction with CB1 (or CB1-like) receptors, located on peripheral endings of sensory neurons involved in pain transmission. Palmitoylethanolamide, which like anandamide is present in the skin, also exhibits peripheral antinociceptive activity during the late phase of pain behavior. Palmitoylethanolamide, however, does not bind to either CB1 or CB2. Its analgesic activity is blocked by the specific CB2 antagonist SR144528, though not by the specific CB1 antagonist SR141716A. Hence a CB2-like receptor was postulated.[citation needed]

Use of antagonistsEdit

CB1 selective antagonists are used for weight reduction and smoking cessation (see Rimonabant). A substantial number of antagonists of the CB1 receptor have been discovered and characterized. TM38837 has been developed as a CB1 receptor antagonist that is restricted to targeting only peripheral CB1 receptors.


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.[1]

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 Gi, 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).[9] 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.[3]

Elimination of clinically undesirable psychotropic effects 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.[citation needed]

The CB1 receptor can also be modulated allosterically synthetic ligands.[10] in a positive[11] and negative[12] manner. In vivo exposure to Δ9THC impairs long-term potentiation and leads to a reduction of phosphorilated CREB.[13]


The CNR1 gene is used in animals as a nuclear DNA phylogenetic marker.[2] This intronless gene has first been used to explore the phylogeny of the major groups of mammals,[14] and contributed to reveal that placental orders are distributed into four major clades: Xenarthra, Afrotheria, Laurasiatheria, and Euarchonta plus Glires. CNR1 has also proven useful at lower taxonomic levels, e.g., in rodents,[15][16] and for the identification of dermopterans as the closest primate relatives.[17]

See alsoEdit


  1. 1.0 1.1 1.2 Entrez Gene: CNR1 cannabinoid receptor 1 (brain).
  2. 2.0 2.1 OrthoMaM phylogenetic marker: CNR1 coding sequence.
  3. 3.0 3.1 3.2 3.3 3.4 PMID 16306385 (PMID 16306385)
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  4. PMID 17535893 (PMID 17535893)
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  5. PMID 15864349 (PMID 15864349)
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  6. PMID 15159284 (PMID 15159284)
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  7. PMID 15249429 (PMID 15249429)
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  8. 8.0 8.1 PMID 9707176 (PMID 9707176)
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  9. PMID 16109430 (PMID 16109430)
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  10. Price MR, Baillie GL, Thomas A, Stevenson LA, Easson M, Goodwin R, McLean A, McIntosh L, Goodwin G, Walker G, Westwood P, Marrs J, Thomson F, Cowley P, Christopoulos A, Pertwee RG, Ross RA (November 2005). Allosteric modulation of the cannabinoid CB1 receptor. Mol. Pharmacol. 68 (5): 1484–95.
  11. Navarro HA, Howard JL, Pollard GT, Carroll FI (April 2009). Positive allosteric modulation of the human cannabinoid (CB1) receptor by RTI-371, a selective inhibitor of the dopamine transporter. Br. J. Pharmacol. 156 (7): 1178–84.
  12. Horswill JG, Bali U, Shaaban S, Keily JF, Jeevaratnam P, Babbs AJ, Reynet C, Wong Kai In P (November 2007). PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats. Br. J. Pharmacol. 152 (5): 805–14.
  13. Fan N, Yang H, Zhang J, Chen C (February 2010). Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo Δ9-THC exposure-impaired hippocampal synaptic plasticity. J. Neurochem. 112 (3): 691–702.
  14. Murphy WJ, Eizirik E, Johnson WE, Zhang YP, Ryder OA, O'Brien SJ (February 2001). Molecular phylogenetics and the origins of placental mammals. Nature 409 (6820): 614–8.
  15. Blanga-Kanfi S, Miranda H, Penn O, Pupko T, DeBry RW, Huchon D (2009). Rodent phylogeny revised: analysis of six nuclear genes from all major rodent clades. BMC Evol. Biol. 9: 71.
  16. DeBry RW (October 2003). Identifying conflicting signal in a multigene analysis reveals a highly resolved tree: the phylogeny of Rodentia (Mammalia). Syst. Biol. 52 (5): 604–17.
  17. Janecka JE, Miller W, Pringle TH, Wiens F, Zitzmann A, Helgen KM, Springer MS, Murphy WJ (November 2007). Molecular and genomic data identify the closest living relative of primates. Science 318 (5851): 792–4.

External linksEdit

  • Cannabinoid Receptors: CB1. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.

Further readingEdit

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  • Hoehe MR, Caenazzo L, Martinez MM, et al. (1991). Genetic and physical mapping of the human cannabinoid receptor gene to chromosome 6q14-q15. New Biol. 3 (9): 880–5.
  • Matsuda LA, Lolait SJ, Brownstein MJ, et al. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346 (6284): 561–4.
  • Gérard C, Mollereau C, Vassart G, Parmentier M (1991). Nucleotide sequence of a human cannabinoid receptor cDNA. Nucleic Acids Res. 18 (23): 7142.
  • Shire D, Carillon C, Kaghad M, et al. (1995). An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. J. Biol. Chem. 270 (8): 3726–31.
  • Bonaldo MF, Lennon G, Soares MB (1997). Normalization and subtraction: two approaches to facilitate gene discovery. Genome Res. 6 (9): 791–806.
  • Kenney SP, Kekuda R, Prasad PD, et al. (1999). Cannabinoid receptors and their role in the regulation of the serotonin transporter in human placenta. Am. J. Obstet. Gynecol. 181 (2): 491–7.
  • Porcella A, Maxia C, Gessa GL, Pani L (2000). The human eye expresses high levels of CB1 cannabinoid receptor mRNA and protein. Eur. J. Neurosci. 12 (3): 1123–7.
  • Mukhopadhyay S, Howlett AC (2001). CB1 receptor-G protein association. Subtype selectivity is determined by distinct intracellular domains. Eur. J. Biochem. 268 (3): 499–505.
  • Murphy WJ, Eizirik E, Johnson WE, et al. (2001). Molecular phylogenetics and the origins of placental mammals. Nature 409 (6820): 614–8.
  • Nong L, Newton C, Friedman H, Klein TW (2002). CB1 and CB2 receptor mRNA expression in human peripheral blood mononuclear cells (PBMC) from various donor types. Adv. Exp. Med. Biol. 493: 229–33.
  • Leroy S, Griffon N, Bourdel MC, et al. (2002). Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1. Am. J. Med. Genet. 105 (8): 749–52.
  • Schmidt LG, Samochowiec J, Finckh U, et al. (2002). Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. Drug and alcohol dependence 65 (3): 221–4.
  • Lastres-Becker I, Cebeira M, de Ceballos ML, et al. (2002). Increased cannabinoid CB1 receptor binding and activation of GTP-binding proteins in the basal ganglia of patients with Parkinson's syndrome and of MPTP-treated marmosets. Eur. J. Neurosci. 14 (11): 1827–32.
  • Petrelli A, Gilestro GF, Lanzardo S, et al. (2002). The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Nature 416 (6877): 187–90.
  • Huang SM, Bisogno T, Trevisani M, et al. (2002). An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc. Natl. Acad. Sci. U.S.A. 99 (12): 8400–5.
  • Ujike H, Takaki M, Nakata K, et al. (2002). CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol. Psychiatry 7 (5): 515–8.
  • Ho BY, Current L, Drewett JG (2002). Role of intracellular loops of cannabinoid CB(1) receptor in functional interaction with G(alpha16). FEBS Lett. 522 (1–3): 130–4.
  • Matias I, Pochard P, Orlando P, et al. (2002). Presence and regulation of the endocannabinoid system in human dendritic cells. Eur. J. Biochem. 269 (15): 3771–8.

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