Cannabinoids interact with each cannabinoid receptor type in the body, sometimes in tandem and sometimes in competition. Each activation gives a response to dampen pain stimuli and reduce inflammation. Cannabinoid receptor types, CB1 and CB2, are proteins embedded in cell membranes. These surface proteins attach to another protein which determines signalling direction: activation or inhibition (tetrahydrocannabinol (THC), for example, activates). The signal that goes out depends on which molecule binds to the receptor. Cannabinoids also activate many other receptors in the human body.
CB1 and CB2 receptors are the most common. The main difference between the two is in their distribution throughout the body: CB1 is highly expressed in neurons within the brain (except the respiratory centre, where it is almost non-existent). CB2 is present in 100-fold lower numbers in the central nervous system and mainly expresses on immune cells, including those of the brain (microglia). The classical effects, in the brain, for CB1 activation are reductions in neuro-transmitter release. CB2 activation dampens microglial activation and reduces neuro-inflammation. These are the basic mechanisms to reduce pain (anti-nociception).
A unique feature of CB1 and CB2 receptors is their ability to “team up” with other neuro-receptors, such as dopamine, opioid, orexigenic (appetite regulator) and adenosine. This cooperation changes their neuro-transmission. In the periphery of the body (outside the central nervous system), reduction of inflammation and neuropathic injury has been primarily ascribed to the activation of CB2. CB2 receptors are present in the peripheral nerves, as well as within the inflamed lining of joints and skin. Reduction of colitis in rodents, for example, has been possible using cannabinoids that act through CB2 receptors. Doctors also managed it with cannabigerol (CBG) acting through CB2.
The GPR55 receptor, a more recently discovered cannabinoid receptor of the non-classical type, regulates neuro-inflammatory responses. GPR55, like CB1 and CB2 attaches to the cellular membrane. It associates with an effector protein inside the cell. GPR55 is part of the central nervous system, expressed in the hypothalamus, thalamus and mid-brain. It modulates anti-nociceptive responses in animals. GPR55 activation can either be pro- or anti-nociceptive depending on the type of injury.
For example, co-activation of CB2 and GPR55 increases microglia activity and neuro-inflammation, while CB2 alone decreases these responses. The anti-inflammatory and pain relieving effects of cannabidiol (CBD) come from how CBD is an inhibitor (antagonist) of GPR55, coupled with the fact that it activates CB2. The effect of THC is a bit cloudier. Knowledge of GPR55 potential in therapeutic applications is still in its infancy and needs many more studies to explore its effects further.
Another non-classical type of cannabinoid receptor is PPARg, which operates by completely different modes of action compared to CB1, CB2 and GPR55. It belongs to a nuclear hormone receptor family, which, when activated, makes alterations at the level of gene expression. Unlike classical receptors that embed in the cellular membrane and exert their actions via activation of signalling cascades within the cell, PPARg directly affects expression of genes involved in inflammation. Scientists have found it in many tissue types, including adipose, muscle, brain and in immune cells. The endocannabinoid anandamide also interacts with PPARg.
Isolation of THC led to the discovery of the Endocannabinoid System (ECS), an atypical neuro-transmission system that modulates release of other neuro-transmitters and participates in many biological processes, including the cascade of inflammatory responses. Due to a myriad of neuro-protective, anti-neuro-inflammatory and anti-oxidant actions, cannabinoids have been cogitated as possible therapeutic agents for neuro-degenerative disorders that combine inflammatory responses, such as Alzheimer’s Disease (AD), Multiple Sclerosis (MS), Huntington and Parkinson Diseases. AD sufferers exhibit increased microglial CB1 and CB2 receptor expression, suggesting a role for cannabinoids.
THC competitively inhibits the enzyme acetylcholinesterase (AChE). A common feature in the AD brain is the presence of AChE. Multiple in vivo studies have also shown CBD reduces neuro-inflammation in dementia and AD. Some suggest the mechanism of action involves CBD acting as PPARg agonist. When CBD activates PPARg, there is reduced gene expression in inflammation from oxidative stress. This decreases neuronal cell death in studies and promotes neurogenesis. A 2017 study in the British Journal of Pharmacology, showed the acid form of THC, tetrahydrocannabinolic acid (THCa), found in the raw plant, has a similar effect on PPARg. THCa activates PPARg with more potency than its decarboxylated counterpart THC. THCa also improves motor deficits, prevents neuro-toxicity and reduces neuro-inflammation.
Cannabinoids also exert their actions on the ion channel, TRPV1. This ion channel is different from usual cannabinoid receptors in that it allows passage of specific ions (sodium and calcium), that trigger a painful burning sensation. Known activators of TRPV1 include temperature above 43oC (which is a protective mechanism that will make us seek strategies to cool off), acidic conditions (such as when we eat a hot chilli pepper), or eating a compound in wasabi. Furthermore, CB1 occurs along with TRPV1. TRPV1 ion channels have desensitisation potential. This explains why we build tolerances to increasingly spicy food.
An interesting application of the interaction between Cannabis, TRPV1 and capsaicin (an extract from chilli peppers with analgesic properties) involves the purported ‘Cannabis Hyperemesis Syndrome’, which is actually Azadirachtin poisoning and not a clinical disorder at all, a complete misdiagnosis and total misnomer! Capsaicin is a neuropeptide releasing agent selective for primary sensory peripheral neurons, producing desensitisation analgesia and as such when used topically, capsaicin aids in controlling peripheral nerve pain.
The severe nausea and vomiting that characterise poisoning by Neem products can be ameliorated in part by rubbing capsaicin on the skin. Cessation of Cannabis treated with Azadirachtin or increasing use of untreated Cannabis are both effective treatments for the toxic effects of the otherwise seemingly harmless Neem. The full characterisation of the interplay between TRPV1, capsaicin and hyperalgesia (enhanced pain response) has not been completed yet, but will prove useful.