CB1 & Opioid Receptors The μ opioid receptor( μOR) is activated by opiates such as morphine and is largely responsible for their pain-blocking effects. Multiple studies have shown that CB1 and μOR form a heteromer with unique properties. Activation of either receptor allows signalling, but activation of both receptors in the heteromer causes a decrease in signalling. This heteromer may also be involved in developing tolerance to the painblocking effects of opiates. The CB1 receptor is expressed in the same cortical neurons as another opioid receptor subtype – the δ opioid receptor( δOR). The δOR is able to reduce anxiety and depressive-like behaviour. Low δOR activity may be responsible for anxiety and depression in people with chronic pain. Many interactions have been demonstrated between CB1 and δOR – they tend to inhibit each other’ s function. If the CB1 receptor is missing, then δOR activity is higher, and vice versa. So it was not much surprise when it was discovered that these receptors interact directly by forming a heteromer. This heteromer was increased in the brains of rats with neuropathic pain, which may contribute to low δOR signalling and anxiety. However, low doses of a CB1 agonist were able to increase δOR activity through a conformation change of the dimer.
CB1 & Serotonin Receptors The serotonin 2A( 5-HT2A) receptor is one of the most fascinating in the brain. It is the receptor activated by hallucinogens such as LSD, psilocin, and mescaline. It also has roles in the effects of antidepressants and antipsychotics. Both the CB1 and 5-HT2A receptors are coexpressed in the same neurons in the amygdala, cerebral cortex, and hippocampus, parts of the brain that regulate emotions, learning, and memory. An interaction between these receptors was long suspected since activation of CB1 by THC and other cannabinoids can modulate several behaviours associated with the 5-HT2A receptor. A 2015 study showed that the CB1 receptor could form a functional heteromer with the 5- HT2A receptor. Activation of CB1 was able to co-activate the 5-HT2A receptor through dimerization. The heteromer was also able to activate different signalling pathways than either receptor on its own. In fact, this heteromer appears responsible for much of the deleterious effects of THC on memory, but also some of the anti-anxiety effect of low THC doses.
CB1 & Dopamine Receptors CB1 and dopamine D2 receptors are coexpressed in the brain in the basal ganglia, an area involved in cognition, motor function, and emotional control. CB1 receptors can form heteromers with D2 receptors in neurons( shown in a 2010 study and earlier studies). Simultaneous stimulation of both receptors resulted in increased heteromer formation and a switch in the intracellular signalling pathway that was activated. Persistent CB1 activation was also associated with a decrease in D2 receptor expression. The functional consequences of this remain unknown, but may have implications for the treatment of Parkinson’ s Disease.
CB1 & Adenosine Receptors A brain region called the dorsal striatum regulates motor activity, cognitive functions, and mood. Most of the neurons within this region express both the CB1 receptor and the adenosine subtype 2A( A2A) receptor. The A2A receptor is famous as the receptor that is inhibited by caffeine. Although there are many different interactions between the adenosine and endocannabinoid systems, a 2017 study showed that some of these interactions can be mediated by formation of a heteromer with CB1. Similar to the μOR, co-activation of both receptors led to a reduction in receptor signalling. This was also accompanied by a