Updated: Apr 18
A quick review of the receptors that mediate the effects of cannabinoids
Cannabis or marihuana is one of the oldest known drugs. Its use goes back to the dawn of time.
The cannabis plant has more than a hundred psychoactive compounds besides delta(9)-tetrahydrocannabinol (THC), the most potent of them. Another important cannabinoids are cannabidiol (CBD), cannabinol (CBN) and cannabigerol (CBG) (Pertwee, 2008).
Cannabinoids bind to three receptors that mediate their effects: CB1, CB2 and GPR55.
All three are G protein-coupled receptors (GPCRs).
G proteins are proteins that serve to carry signals inside the cells. They are formed by three subunits, α, β and γ. Normally, the G protein is attached to the GPCR in the inside of the cell membrane. When the GPCR binds its neurotransmitter, the G protein dissociates, with the α and the βγ subunits going separate ways to carry signals inside the cell.
There are different G proteins. They have the same βγ subunits but different α subunits. Each α subunit activates a different second messenger system. Like the opioid receptors, CB1 and CB2 act through the inhibitory αi G proteins, which decrease the synthesis of the second messenger cyclic AMP (cAMP). In neurons, this leads to a decrease in the firing of action potentials and a decrease in neurotransmitter release.
CB1 receptors mediate most of the psychoactive effects of THC: analgesia, euphoria and sometimes paranoia. It is the most abundant GPCR in the brain, being found in most brain regions.
CB2 receptors were initially thought to exist only in non-brain tissues, like immune cells. However, more recently it was found in the brain, where it modulates the actions of CB1. They have important functions in the immune system and other organs of the body.
GPR55 was an ‘orphan’ receptor, that is, a receptor whose gene was found first, before its ligand was known (Lauckner et al., 2008). GPR stands for ‘G protein-coupled receptor’. It signals through Gq and G12 proteins, releasing calcium from intracellular stores and inhibiting M current potassium channels (Lauckner et al., 2008). All that means that it excites neurons, instead of inhibiting them like CB1 and CB2 receptors.
GPR119 and GPR18 are other orphan receptors that may also be cannabinoid receptors.
TRPV1 (the capsaicin receptor), TRPV2 and TRPV3 are other receptors that can be activated by cannabinoids and endocannabinoids (Santha et al., 2010). They act as heat sensors in the skin, with TRPV1 detecting burning temperatures and TRPV2 and TRPV3 detecting milder temperatures. But they are also present in neurons in the central nervous system, playing roles still not well understood.
CB1 and CB2 agonists
There are many synthetic compounds that are agonists of CB1 and CB2 receptors (Patel and Hillard, 2006; Bow and Rimoldi, 2016).
WIN 55,212-2 is one of the oldest of these compounds. It is an agonist of both CB1 and CB2 receptors.
Arachidonyl-2'-chloroethylamide (ACEA) is a selective agonist of CB1 receptors.
CB 65, HU 308 and JWH 133 are selective agonists of CB2 receptors.
Abnormal-cannabidiol, ML 184 and O-1602 are selective agonists of GPR55 (Ross, 2009).
These compounds are important tools for discriminating the effects of these three receptors.
Constitutive activity of CB1 and CB2 receptors
Like the µ-opioid receptor, CB1 and CB2 receptors have constitutive activity. This means that they have a little bit of activity, even when they do not bind an agonist, activating their associated G proteins to a certain extent.
Therefore, there are compounds that act as inverse agonists of these receptors, that is, not only they inhibit the effect of the agonists, but are also able to inhibit the constitutive activity.
Most of the substances identified as CB1 receptors antagonist, like rimonabant (or SR 141716A), AM 251 and AM 281, are in fact inverse agonists. AM 630 and GP 1a are inverse agonists of CB2 receptors.
What is important about these compounds is that scientists have the ability to selectively block each one of the three cannabinoid receptors in order to determine how they contribute to the effects of THC, CBD and the endocannabinoids. However, since these compounds are inverse agonists, they would also block the constitutive activity that CB1 and CB2 receptors may have in the absence of any agonist.
Bow EW, Rimoldi JM (2016) The Structure-Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation. Perspect Medicin Chem 8:17-39.
Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K (2008) GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci U S A 105:2699-2704.
Patel S, Hillard CJ (2006) Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther 318:304-311.
Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199-215.
Ross RA (2009) The enigmatic pharmacology of GPR55. Trends Pharmacol Sci 30:156-163.
Santha P, Jenes A, Somogyi C, Nagy I (2010) The endogenous cannabinoid anandamide inhibits transient receptor potential vanilloid type 1 receptor-mediated currents in rat cultured primary sensory neurons. Acta Physiol Hung 97:149-158.