Cannabinoid receptor type 1
Cannabinoid receptor 1 (brain)
|RNA expression pattern|
The cannabinoid receptor type 1, also known 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.
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).
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.
In the liver, activation of the CB1 receptor is known to increase de novo lipogenesis, 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.
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.
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.
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
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 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). 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.
- ↑ 1.0 1.1 1.2 Entrez Gene: CNR1 cannabinoid receptor 1 (brain).
- ↑ 2.0 2.1 2.2 2.3 2.4 Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R (2006). "The emerging role of the endocannabinoid system in endocrine regulation and energy balance". Endocr. Rev. 27 (1): 73–100. doi:10.1210/er.2005-0009. PMID 16306385.
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- ↑ 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. doi:10.1038/sj.bjp.0705839. PMID 15159284.
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