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The cannabinoid 1 receptor (CB1) and cannabinoid 2 receptor (CB2) are found throughout the body in many tissues, playing an essential role in the endocannabinoidome. CB1 receptors are found primarily in the nervous system and the CB2 receptors are found throughout the body, with lesser representation in the central and peripheral nervous systems. The CB1 receptor’s function is primarily to control neurotransmitter release at synapses such as glutamate and gamma amino butyric acid (GABA) throughout the nervous system. The CB2 receptors are more involved in the control of cellular inflammation in immune cells and synoviocytes of the joint, as well as other organ functions. The endogenous ligands for these receptors are fatty acid derived molecules that are constantly being released from cell membranes. Activating these receptor systems provides neurological tone and homeostasis within organ systems. The most prominent and well-studied endocannabinoids are arachidonoylethanolamide (AEA; also known as anandamide) and 2-arachidonyl-glycerol (2-AG), which are constantly being released from cell membranes. These endocannabinoids are rapidly metabolized by hydrolase enzymes to the native fatty acid known as arachidonic acid, which is re-incorporated into cell membranes rapidly or utilized for other cellular functions.

The endocannabinoidome is an extension of the endocannabinoid system due to the multimodal action at receptors outside of the CB1 and CB2 receptors. The primary exogenous cannabinoid that interacts and activates the CB1 and CB2 receptor is a chemical synthesized from Cannabis know as delta 9-tetrahydrocannabinol (THC). Other cannabinoids such as cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromene (CBC), cannabichromenic acid (CBCA), and tetrahydrocannabinolic acid (THCA) are not agonists of these receptors, thereby not eliciting any psychotropic activity. In some cases they are considered antagonists of these receptors.  These cannabinoids influence the CB1 and CB2 receptor, signaling only at very high concentrations and more often as antagonists. They have actions at other receptors involved in neurotransmission within neurons, resulting in an expansion of their functions, termed the “Endocannabinoidome.”  These other receptor systems include a range of targets found in neurons and many other cells of the body. They influence both neurotransmission and potentially immune cell regulation, which are two targets of the pain response as well as many other disease processes. 

Dampening of the inflammatory response is critical to any inflammatory disease across organ systems whether GI, nervous system, skin or arthritis.

One of the primary receptor systems is the transient receptor potential channels also known as the villinoid receptors and other related channels (TRPV, TRPA, TRPM) are involved in the sensation of pain. They are activated or deactivated by exogenous cannabinoids with eventual desensitization of the channel hindering the neuronal signaling upstream for the cognitive perception of pain through mechanisms likely through hindering ion channels and influencing calcium influx as potential mechanisms for neuronal regulation.

Similarly exogenous hemp cannabinoids are also involved in the transmission of pain through heightened signaling in the central nervous system at the glycine receptor.  These glycine receptors are stimulated by CBD and CBDA causing a hyperpolarization of neurons which dampens their ability to transmit signals through the central nervous system, which hinders the overall cognitive perception of pain.

The cognitive threshold for pain perception involves many receptor systems including the 5 hydroxytryptophan (5-HT) system. Endogenous endocannabinoids and exogenous hemp derived cannabinoids influence the subvariant 5HT1A and 5HT2A receptor systems similar to the neurotransmitter serotonin (aka 5HT), which modulates pain perception and feelings of overall wellness.  Similarly, there are exogenous nucleotide transporters that will allow for adenosine transport into neurons that cannabinoids interact with to diminish adenosine uptake in neurons providing a global decrease in cyclic adenosine monophosphate. This is an important mechanism in neural signaling most often related to seizure like activities, rather than the pain responses based on the current literature. There are also potential interactions with the natural endocannabinoids that are continuously released by active neurons. In these interactions, CBD and CBDA heighten the availability of the natural endocannabinoids (anandamide and 2-AG) through inhibition of the hydrolases in neurons that limit their activity and crosstalk between neurons. These endocannabinoids traditionally interact with the CB1 and CB2 receptors providing heightened cannabinoid tone, which is important for pain relief and feelings of angst.

The lesser known or studied g-protein receptors interact with cannabinoids such as CBD and CBDA. These receptors are part of the the g-protein orphan receptor system. Like the TRP system, the g-protein orphan receptor system is involved in calcium influx into cells for neurotransmission as well as cytokine release in inflammatory cells. GPR55 primarily interact with CBD and CBDA to alter the CB1 and CB2 signaling from endogenous cannabinoids in the body, thereby dampening the neuronal signaling associated with pain. In line with the inflammatory response, the peroxisomal proliferation activation receptor (PPAR) system is a well-known nuclear receptor family that is activated by CBD and CBDA to diminish the immune system’s ability to make pro-inflammatory cytokines involved in the inflammatory response.  Dampening of the inflammatory response is critical to any inflammatory diseases across organ systems whether GI, nervous system, skin, or arthritis. Lastly, The GABA receptors are important in transmission of the pain signal from the periphery and through the central nervous system. CBD and CBDA also influences this transmission of signaling from the periphery to the central nervous system, yet the mechanisms are poorly elucidated at this juncture regarding their relationship to pain transmission.

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