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cannabinoid receptor 1 (brain)
Symbol(s): CNR1 CNR
Locus: 6 q14 -q15
EC number [1]
EntrezGene 1268
OMIM 114610
RefSeq NM_033181
UniProt P21554


cannabinoid receptor 2 (macrophage)
Symbol(s): CNR2
Locus: 1 p
EC number [2]
EntrezGene 1269
OMIM 605051
RefSeq NM_001841
UniProt P34972


The cannabinoid receptors are a class of receptors under the G-protein coupled receptor superfamily. Their ligands are known as cannabinoids or endocannabinoids depending on whether they come from external or internal (endogenous) sources, respectively.They are components of the endocannabinoid system


There are currently two known subtypes, CB1[1][2] which is expressed mainly in the brain, but also in the lungs, liver and kidneys and CB2 which is mainly expressed in the immune system and in hematopoietic cells. Mounting evidence suggests that there are novel cannabinoid receptors[3] that is, non-CB1 and non-CB2, which are expressed in endothelial cells and in the CNS. In 2007, the binding of several cannabinoids to a GPCR in the brain was described.[4]

The protein sequences of CB1 and CB2 receptors are about 44% similar.[5] In addition, minor variations in each receptor have been identified. Cannabinoids bind reversibly and stereo-selectively to the cannabinoid receptors. The affinity of an individual cannabinoid to each receptor determines the effect of that cannabinoid. Cannabinoids that bind more selectively to certain receptors are more desirable for medical usage.


Main article: Cannabinoid receptor type 1

Cannabinoid receptor type 1 (CB1) receptors are thought to be the most widely expressed G-protein coupled receptors in the brain. This is due 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.

They are also found in other parts of the body. For instance, in the liver, activation of the CB1 receptor is known to increase de novo lipogenesis,[6] 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.[7]

A study done on CB1 knockout mice (genetically altered mice who cannot produce CB1) showed an increase in mortality rate. They also displayed suppressed locomotor activity as well as hypoalgesa (decreased pain sensitivity). The CB1 knockout mice did respond to Delta9-Tetrahydrocannabinol. This shows that either CB2 or unknown cannabinoid receptors also have pharmacologic significance[8] .


Main article: CB2 receptor

CB2 receptors are mainly expressed on T cells of the immune system, on macrophages and B cells, and in hematopoietic cells. They also have a function in keratinocytes, and are expressed on mouse pre-implantation embryos. It is also expressed on peripheral nerve terminals. Current research suggests that these receptors play a role in nociception, or the perception of pain. In the brain, they are mainly expressed by microglial cells, where their role remains unclear.

Other cannabinoid receptorsEdit

The existence of additional cannabinoid receptors has long been suspected, due to the actions of compounds such as abnormal cannabidiol which produce cannabinoid-like effects on blood pressure and inflammation, yet do not activate either CB1 or CB2.[9][10][11] Recent molecular biology research suggested that the orphan receptor GPR55 should in fact be characterised as a cannabinoid receptor, on the basis of sequence homology at the binding site. Subsequent studies showed that GPR55 does indeed respond to cannabinoid ligands.[12][13] This profile as a distinct non-CB1/CB2 receptor which responds to a variety of both endogenous and exogenous cannabinoid ligands, has led some groups to suggest GPR55 should be categorised as the CB3 receptor, and this re-classification may follow in time.[14] However this is complicated by the fact that another possible cannabinoid receptor has been discovered in the hippocampus, although its gene has not yet been cloned,[15] suggesting that there may be at least two more cannabinoid receptors to be discovered, in addition to the two that are already known.


Cannabinoid receptors are activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body as cannabis or a related synthetic compound.

After the receptor is engaged, multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly inhibited 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).[16] 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.[16]

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 (2-AG)— produce most of their effects by binding to both the CB1 and CB2 cannabinoid receptors. While the effects mediated by CB1, mostly in the CNS, have been thoroughly investigated, those mediated by CB2 are not equally well defined.


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.[17]

Cardiovascular activityEdit

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.

The hypotension in hemorrhaged rats was prevented by the CB1 antagonist SR 141716A. Recently the same group found that anandamide-induced mesenteric vasodilation is mediated by an endothelially located SR 141716A-sensitive "anandamide receptor," distinct from the CB1 cannabinoid receptor, and that activation of such a receptor by an endocannabinoid, possibly anandamide, contributes to endotoxin-induced mesenteric vasodilation in vivo. The highly potent synthetic cannabinoid HU-210, as well as 2-AG, had no mesenteric vasodilator activity. Furthermore it was shown that mesenteric vasodilation by anandamide apparently has 2 components, one mediated by a SR 141716-sensitive non-CB1 receptor (located on the endothelium) and the other by an SR 141716A-resistant direct action on vascular smooth muscle.

The production of 2-AG is enhanced in normal, but not in endothelium-denuded rat aorta on stimulation with Carbachol, an acetylcholine receptor agonist. 2-AG potently reduces blood pressure in rats and may represent an endothelium-derived hypotensive factor.


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 (rimonabant). Hence a CB2-like receptor was postulated.

In experiments on mice, a chemical designated JZL184 that inhibits a naturally occurring enzyme MAGL from degrading a pain relieving endocannabinoid called 2-arachidonoylglycerol (AG) increases the brain concentration of AG and thereby induces analgesia.[18][19]

Cannabinoid treatmentsEdit

Main article: Medical cannabis

Cannabis sativa preparations have been known as therapeutic agents against various diseases for millennia.[20] The native active constituent, Δ9-tetrahydrocannabinol9-THC) was found to be the principal mediator of the effects of cannabis.[21] Synthetic Δ9-THC is prescribed today under the generic name Dronabinol, to treat vomiting and for enhancement of appetite, mainly in AIDS patients.

Several synthetic cannabinoids have been shown to bind to the CB2 receptor with a higher affinity than to the CB1 receptor.[22] Most of these compounds exhibit only modest selectivity. One of the described compounds, a classical THC-type cannabinoid, L-759,656, in which the phenolic group is blocked as a methyl ether, has a CB1/CB2 binding ratio > 1000.[23] The pharmacology of these agonists has yet to be described.

Certain tumors, especially gliomas, express CB2 receptors. Guzman and coworkers have shown that Δ9-tetrahydrocannabinol and WIN-55,212-2, two non-selective cannabinoid agonists, induce the regression or eradication of malignant brain tumors in rats and mice.[24] CB2 selective agonists are effective in the treatment of pain, various inflammatory diseases in different animal models,[25][26] osteoporosis[26] and atherosclerosis.[27] CB1 selective antagonists are used for weight reduction and smoking cessation (see Rimonabant). Activation of CB1 provides neuroprotection after brain injury.[28]

Several studies have also concluded that certain cannabinoids might have the ability to prevent Alzheimer's disease.[29]

NMR Imaging Edit

The protein image was created using nuclear magnetic resonance to determine crystal structure. The picture represents the fourth cytoplasmic loop of the CB1 cannabinoid receptor.

See also Edit


  1. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346 (6284): 561–4.
  2. Gérard CM, Mollereau C, Vassart G, Parmentier M (1991). Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem. J. 279 ( Pt 1): 129–34.
  3. Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, Liu J, Kunos G (2005). Evidence for novel cannabinoid receptors. Pharmacol. Ther. 106 (2): 133–45.
  4. Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ (2007). The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol. 152 (7): 1092–101.
  5. Munro S, Thomas KL, Abu-Shaar M (1993). Molecular characterization of a peripheral receptor for cannabinoids. Nature 365 (6441): 61–65.
  6. Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L, Kunos G (2005). Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J. Clin. Invest. 115 (5): 1298–305.
  7. Godlewski G, Malinowska B, Schlicker E (2004). Presynaptic cannabinoid CB1 receptors are involved in the inhibition of the neurogenic vasopressor response during septic shock in pithed rats. Br. J. Pharmacol. 142 (4): 701–8.
  8. Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI TI (1999). Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice.
  9. Járai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, Razdan RK, Zimmer A, Kunos G. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proceedings of the National Academy of Sciences USA. 1999 Nov 23;96(24):14136-41. PMID 10570211
  10. Ho WS, Hiley CR. Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery. British Journal of Pharmacology. 2003 Apr;138(7):1320-32. PMID 12711633
  11. McHugh D, Tanner C, Mechoulam R, Pertwee RG, Ross RA. Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2. Molecular Pharmacology. 2008 Feb;73(2):441-50. PMID 17965195
  12. Johns DG, Behm DJ, Walker DJ, Ao Z, Shapland EM, Daniels DA, Riddick M, Dowell S, Staton PC, Green P, Shabon U, Bao W, Aiyar N, Yue TL, Brown AJ, Morrison AD, Douglas SA. The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects. British Journal of Pharmacology. 2007 Nov;152(5):825-31. PMID 17704827
  13. Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ. The orphan receptor GPR55 is a novel cannabinoid receptor. British Journal of Pharmacology. 2007 Dec;152(7):1092-101. PMID 17876302
  14. Overton H, Babbs A, Doel S, Fyfe M, Gardner L, Griffin G, Jackson H, Procter M, Rasamison C, Tang-Christensen M. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metabolism 2003; 3(3):167-175.
  15. De Fonseca FR, Schneider M. The endogenous cannabinoid system and drug addiction: 20 years after the discovery of the CB1 receptor. Addiction Biology 2008; 13:143-146.
  16. 16.0 16.1 Demuth DG, Molleman A (2006). Cannabinoid signalling. Life Sci. 78 (6): 549–63.
  17. Mathison R, Ho W, Pittman QJ, Davison JS, Sharkey KA (2004). Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats. Br. J. Pharmacol. 142 (8): 1247–54.
  18. Cannabis-like drug dims pain without the high. News. COSMOS magazine. URL accessed on 2008-12-02.
  19. Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavón FJ, Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF (November 2008). Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat. Chem. Biol. 5: 37.
  20. Pacher P, Bátkai S, Kunos G (2006). The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58 (3): 389–462.
  21. Gaoni Y, Mechoulam R (1964). Isolation, structure and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86 (8): 1646–1647.
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  23. Ross RA, Brockie HC, Stevenson LA, Murphy VL, Templeton F, Makriyannis A, Pertwee RG (February 1999). Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656, and AM630. Br. J. Pharmacol. 126 (3): 665–72.
  24. Galve-Roperh I, Sánchez C, Cortés ML, del Pulgar TG, Izquierdo M, Guzmán M (2000). Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat. Med. 6 (3): 313–9.
  25. Whiteside GT, Lee GP, Valenzano KJ (2007). The role of the cannabinoid CB2 receptor in pain transmission and therapeutic potential of small molecule CB2 receptor agonists. Curr. Med. Chem. 14 (8): 917–36.
  26. 26.0 26.1 Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I (2006). Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc. Natl. Acad. Sci. U.S.A. 103 (3): 696–701.
  27. Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard JL, Mach F (2005). Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 434 (7034): 782–6.
  28. Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E (2001). An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413 (6855): 527–31.
  29. Ramíirez, B. G., C. Blázquez, T. Gómez del Pulgar, M. Guzmán, and M. L. de Ceballos (2005). Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. Journal of Neuroscience 25 (8^): 1904–1913.

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