The mechanism described suggests new treatment methods for chronic pain that address its cause, not its symptoms like existing treatments. The correlation between the number of hyperexcitable immature neurons in the spinal cord and chronic pain indicates that a treatment that aims to reduce that number of immature neurons could also inhibit chronic pain. This can be achieved pharmacologically by accelerating the differentiation and maturation of immature neurons. 

Neuronal differentiation is a complex process that involves hundreds of proteins. This explains the variety of genes identified to play a role in chronic pain. Identifying and addressing the malfunction of each individual gene in each individual would be logistically very difficult. However, the dysfunctionality of many of these proteins may be overcome by using one of several pathways known to induce neuronal differentiation.  For example, the neurotrophin family of receptors is a typical target for that purpose. 

The TrkB Receptor: A New Target for Chronic Pain Therapy

TrkB is one of the four neurotrophin receptors. TrkB induces neuronal differentiation and maturation and also has additional roles essential for neuronal viability and functionality. For example TrkB activation is thought to play a role in learning and memory. The natural endogenous activator of TrkB is BDNF (Brain-Derived Neurotrophic Factor), a large polypeptide released by cells in the nervous system. Due to its role in learning and memory and neuronal survival, BDNF has been tried (with inconclusive results) as a therapy for Alzheimer’s Disease.

However, in our studies BDNF proved to be an effective treatment for chronic pain (US Patent 10,398,760; 2019). In rats and mice treated with BDNF after severe sciatic nerve injury, the duration of pain was reduced from 3 months to 3-4 days, concurrently with the substantial reduction in the number of immature neurons. This supports the mechanism that immature neurons are responsible for extended periods of pain. 

The therapeutic use of BDNF is difficult because it is a large peptide with reduced stability. BDNF is generated within the nervous system for immediate use over short distances and it degrades very rapidly under the action of cellular enzymes. Our goal is to develop small, stable drug molecules that can activate the TrkB receptor similarly to BDNF  and reduce the duration and intensity of pain. 

Flavones: A New Class of Chronic Pain Medication

Some compounds in the flavone class have structural similarity with BDNF and can also activate the TrkB receptor. These are small molecules with good stability that can be used as therapeutic agents instead of BDNF. We have already demonstrated the ability of flavones to eliminate chronic pain in a manner almost identical to BDNF. 

Interestingly, herbal extracts rich in specific flavones have been used in traditional medicine since prehistoric times as a treatment for pain. A few of these flavones have been recently identified, for example baicalein (found in Chinese skullcap), naringenin (grapefruit), chrysin (passion flower) and others. These identified natural compounds are only mildly effective and very expensive to isolate.  

Our goal is to develop new more effective therapies for chronic pain based on the mechanism and discoveries described above.  We have developed a new technology (patent pending) for the efficient discovery and optimization of new compounds in this class as treatments for chronic pain.