When we think about the endocannabinoid system (ECS) (the body's system of neurotransmitters, receptors, and enzymes that are highjacked by the chemicals in cannabis) we tend to think about four pieces of it: the neurotransmitters (NTs) anandamide and 2-AG and the receptors CB1 and CB2. Out-dated neuroscience theories posited that one neuron sends one NT and one NT can bind only to one receptor. While this may be (putatively) true for many NTs, like dopamine and serotonin, some NTs can interact with receptors outside of their "class". Also, some receptors can be activated by several different NTs. In scientific parlance, we called this "promiscuity" And guess what? It turns out that our ECS can be pretty promiscuous indeed!
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Students in Neuroscience 101 are taught the "lock and key" relationship between NTs and their receptors. Well, imagine you have a skeleton key. That is what neuroscientists are starting to discover about our ECS; endocannabinoids are capable of not only activating CB1/2 but many other receptors as well. The implications for these interactions are just now starting to emerge. Let me introduce to you some of these "promiscuous" molecules busy soliciting in our ECS.
Transient receptor potential vanilloid (TRPV1) is a receptor that is activated by several NTs including anandamide. TRPV1 is promiscuous. Among its ligands are ECs and THC. TRPV1 activation in the spinal cord appears to regulate pain. There is a high degree of colocalization of CB1 and TRPV1 receptors on the cellular membrane. EC activity at this receptor could play a role in analgesia (pain reduction). GPR55 is another promiscuous receptor that is also involved in pain signaling. Synthetic ECs such as rimonabant and O-1602 bind to GPR55 and decrease neuropathic pain in rodents. While it is unknown whether ECs bind to GPR55, the fact that synthetic ECs are able to suggest that they may.
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ECs themselves are also capable of binding to receptors other than the "classic" CB1/2 receptors. Gamma-butyric acid (GABA) is the main inhibitory NT in the brain. The EC 2-AG can bind to GABA-A receptors to inhibit GABA release. Another receptor for an affinity for endocannabinoids is glycine. Glycine is similar to GABA but located mainly in the spinal cord and the peripheral nervous system. The phytocannabinoid THC has been shown to bind to glycine and potentiate their firing rate. This binding to the glycine receptor could mediate THC's analgesic effects from within the spinal cord.
This promiscuity is actually a good thing. It gives scientists more possible targets to treat various ailments, such as neuropathic pain. Not only do these findings provide novel clinical treatments, but it helps us to better understand this complex and dynamic system within us known as the ECS.
Sources: www.leafly.com, LabRoots.com, British Journal of Pharmacology, Neuroscience, Vol 2, www.khanacademy.org, Pain, https://en.wikipedia.org/wiki/TRPV, Molecular Pain, Life Sciences, Cannabis and Cannabinoid Research, Nature Chemical Biology