Delivering Cannabis Directly to the Site
New research is delving into allosteric sites that bind cannabinoids and then change shape to allow for additional bindings and specific pain relief.
Chronic pain is one of the most pressing public health concerns and it has been estimated that about 10% of the North American population is stuck in a pain cycle that greatly impacts their life. Compound this with the opioid epidemic, the response to which has been to cut patients off meds that they need to function, and there’s a epic crisis. The idea that cannabis may be a solution to this giant-sized problem has been supported by scientific evidence. And, recently, there is this new idea that pain relief from cannabis can be targeted to the specific tissues.
Image credit: Anthony Pitch
Cannabis-Pain Relief Research is Still Young
It has only been three decades since the discovery of the key components of the ECS: CB1 and CB2 receptors, endogenous cannabinoids, and a set of enzymes that make them and break them apart. Soon thereafter, it was found that the ECS operates through pathways that regulate pain control, making it an attractive candidate for pain treatment.
Image credit: Wut ti kit
The initial hypothesis was that by using plant-based, or synthesized cannabinoids, CB1 receptor activation would follow, which would then lead to pain relief. It was also thought that manipulation of the enzymes that make and degrade endocannabinoids would have also therapeutic potential.
Big Pharma came up with Nabilone and Dronabinol, which did work pretty well. A mix of THC and CBD from cannabis strains worked better and are now indicated for spasticity, pain and nausea. However, other times these efforts have not proven fruitful.
What lessons have we learned? Primarily, it is now recognized that the ECS components are distributed throughout the whole body, both centrally (brain and spinal cord) and peripherally (tissues such as skin, liver, and immune cells etc.). That has been a critical piece in narrowing the target board for treating different conditions with cannabis.
Getting Cannabinoids to Target
Secondly, across these different sites, binding of ligands to cannabinoid receptors sometimes leads to their activation and sometimes to inhibition. In practical terms, this means that in designing therapeutics for pain relief, using substances such as THC, that will bind to cannabinoid receptors, doesn’t necessarily mean that it will lead to pain relief.
This is because cannabinoids will bind to all available cannabinoid receptors, both centrally and peripherally. Some actions may be pain relieving, while others may not.
Recently scientists tried to solve this dilemma by targeting cannabinoid receptors belonging to a class of receptors called G-protein coupled receptors. These have multiple parts and binding sites. We thought that ligands, such as cannabinoids, activated the receptors by binding to the main binding sites.
However, scientists have uncovered that a different set of sites, called allosteric sites, can modify the shape of the receptor and thereby hide or uncover additional areas for binding.
In doing so, the receptor can either increase or decrease the effect of the cannabinoid. Importantly, the traditional binding sites tend to be the same across all cannabinoid receptors throughout the body (for CB1 or CB2), while the allosteric sites seem to vary across the sites in the body, which would create receptor subtypes with distinct properties throughout the body tissues and organs.
What Do We Do From Here?
The implications of these discoveries, for the field of pain relief, rest in the fact that cannabinoid receptors have unique allosteric sites in the brain versus the periphery. This means that pharmacotherapeutic strategies can be then be aimed selectively – to only target those located near the pain receptors.
A team of researchers has recently put this strategy to the test and developed a cannabinoid receptor allosteric modulator which has reduced neuropathic and inflammatory pain in animal trials. The work continues…
This discovery will certainly open up new, more targeted avenues for pain relief therapeutics, which would be greatly beneficial for all, but in particular to patients with opioid tolerance.