Chemotherapeutics pain relief beyond THC: a novel mechanism

Evidences have shown that chemotherapeutics induce peripheral neuropathic pain, an hypersensitization of the conducting nerves characterized by shooting or burning sensation following gentle touch (which would not provoke pain in healthy individuals).

This condition is also said allodynia, described as a lower threshold to pain, which is often caused as a secondary symptoms to many illnesses, such as cancer, diabetes, multiple sclerosis but can also be caused by human intervention, due to medicines (like chemotherapeutics) or in post-op (i.e. dental surgery).

The chemo drugs mostly associated with Chemotherapy-induced peripheral neuropathy (CIPN) are:

• Platinum drugs like cisplatin, carboplatin, and oxaliplatin
• Taxanes including paclitaxel (Taxol®), docetaxel (Taxotere®), and cabazitaxel (Jevtana®)
• Epothilones, such as ixabepilone (Ixempra®)
•  Plant alkaloids, such as vinblastine, vincristine,vinorelbine, and etoposide (VP-16)
•  Thalidomide (Thalomid®), lenalidomide (Revlimid®), and pomalidomide (Pomalyst®)
•  Bortezomib (Velcade®) and carfilzomib (Kyprolis®)
•  Eribulin (Halaven®)

It has been widely proved that activation of the CB1 receptors (Classic cannabinoid receptors) provides relief from pain. (Read here to check the mechanism of function)

However, direct activation at this receptor causes the psychotropic effects that have precluded Cannabis access to most Countries.

The laboratory of Dr Pertwee (Aberdeen University, UK)  and colleagues have found an interesting alternative by using a method that overcome side effects associated with THC-like effects.

They investigated a compound, GAT211, which modulates the activity at CB1 receptors allosterically; in other words, whilst the THC molecule binds directly to the receptor (think LEGO elements fitting perfectly into each other), GAT211 binds elsewhere on the surface of the receptor, inducing conformational changes in the receptors (said orthosteric binding).

Cannabinoid receptors, such as CB1, belong to a very large family of receptors that is called G-Protein Coupled Receptors (or GPCRs in short).

The mechanism of function of this receptor family requires a brief introduction in order to understand better GAT211 actions.

You can imagine the receptors (usually at the surface of cells) as door locks.

When the correct key (which in pharmacology is said ligand) is inserted in the receptor, a chain of events is triggered and many proteins get involved so that physiological effects take place.

Thus, GAT211 is capable to increase signals downstream from the receptors, causing physiological events, but to does not operate directly as a key-and-lock mechanism.

Rather, this compound induces increased levels of Anandamide, an endogenous cannabinoid (the natural analgesic produced by our own bodies) which activate CB1 receptors without provoking the side effects related to exogenous compounds (such as Cannabis).

The research group found that activation of CB1 receptors followed a concentration-dependent manner of GAT211, (the more GAT211, the more activation of CB1).

Such activation, as we aforementioned, was not due to direct activation of the compound GAT211, but by Anandamide.

Literature indicates that activation of CB1 receptors induces anti-nociception (analgesic effect), hypothermia (cold sensation), motor difficulties and catalepsy.

Following pharmacological studies, the researchers observed animals for physiological effects with GAT211.

They tested body temperature, which remained stable, and Rotarod (a motor function test inspired by the classic running wheel).

Rotarod

The results were very positive: no animal experienced catalepsy, nor hypothermia and could maintain a very good balance on the running wheel. More interestingly, the rodents treated with GAT211 were insensitive to pain compared to their placebo littermates.

Delta-9 THC is very efficacious at reducing allodynia, but it fails to attenuates pain following chronic doses, as it induces tolerance (henceforth the doses must be increased to attenuates pain).

Conversely, GAT211 does not produce tolerance.

Moreover, GAT211 is not addictive as it has been demonstrated by place-preference studies.

In place-preference studies the animals have access to two chambers, made very distinguishable one from the other.

They are dosed with a compound in one of the two chambers so that they learn to associate chamber A with the sensations related to the given compound.

Following administration in chamber A of morphine, which is mostly used in the clinics for pain management, the animals are given the choice of going in any of the two chambers.

9 out of 10 times they choose chamber A over chamber B, showing high addictive properties of the substance.

When the same experiments were done with GAT211, the animals did not show a preference pattern, and chamber A and B were chosen at the same rate.

Pain management is one of the biggest unmet clinical needs and cannabinoid circuitry regulation is an incredible resource for the clinics.

There are thousands studies on cannabinoids that offer a valid alternative to Cannabis plant but are still topic of rejection due to the unfortunate name “cannabinoids” which relegate such vast category of medicines as dangerous or somehow illicit compounds.

You can make a difference for all those suffering an illness that could be treated by cannabinoids by sharing real information.

The hypocrisy upon this topic will end only when the truth will be out in the public.

Visovsky C, Collins M, Abbott L, Aschenbrenner J, Hart C. Putting evidence into practice: Evidence-based interventions for chemotherapy-induced peripheral neuropathy. Clin J Oncol Nurs.(2007);11:901-913.

Wickham R. Chemotherapy-induced peripheral neuropathy: A review and implications for oncology nursing practice. Clin J Oncol Nurs.(2007);11:361-376.