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