BRAF identified as novel target for neuropathic pain treatment

Researchers at The University of Texas MD Anderson Cancer Center have identified a potential new target for treating chronic pain caused by nerve damage.

The study found that BRAF, a protein commonly associated with cancer, plays an important role in the development and maintenance of neuropathic pain. In preclinical models, drugs that inhibit BRAF reduced pain sensitivity following nerve injury. The findings suggest that existing cancer medicines targeting BRAF could potentially be repurposed to treat chronic nerve pain.

“Our findings identify the cancer-promoting protein BRAF as a key driver of pathological pain signalling following nerve injury,” said Hui-Lin Pan, Endowed Chair of Anesthesiology and Perioperative Medicine. “Because BRAF inhibitors are already approved for cancer treatment, this discovery raises the possibility of rapidly repurposing existing therapies to reduce the level of pain signals entering the spinal cord and improve patient quality of life.” 

How nerve damage drives pain

Neuropathic pain can result from nerve injury or disease as well as some cancer treatments. It can be severe and persistent and often responds poorly to conventional pain medicines. 

The researchers focused on NMDA receptors, proteins found in the brain and spinal cord that help nerve cells communicate. Following nerve injury, these receptors can become excessively active, amplifying pain signals travelling through the nervous system. 

The researchers investigated whether BRAF was involved in regulating this process using preclinical models of nerve injury, observing that BRAF moved from peripheral sensory nerve cells to their terminals within the spinal cord. Once there, it activated molecular signalling pathways that increased NMDA receptor activity.

They also identified a relationship between BRAF signalling proteins and NMDA receptors in human spinal cord samples, providing further evidence that the pathway could be relevant to human pain.

These findings led the team to investigate whether blocking BRAF could reduce pain sensitivity.

Existing cancer drugs reduce pain

In preclinical models, the BRAF inhibitor vemurafenib and the MEK inhibitor selumetinib reduced sensitivity to touch, pressure and heat following nerve injury. The drugs did not alter normal responses in models without nerve damage.

The researchers also found that deleting the Braf gene from their mouse model resulted in less persistent pain sensitivity. Conversely, directly activating BRAF caused pain sensitivity in models without nerve injury.

Together, these results suggest that BRAF may have a role in both initiating and maintaining neuropathic pain.  

Potential for drug repurposing

The findings could have huge significance as BRAF inhibitors are already approved for treating certain cancers. However, the research remains at a preclinical stage and further work is needed before the approach can be tested in people with chronic nerve pain.

Researchers will need to establish appropriate doses and delivery methods as well as assess potential side effects. They also want to determine exactly how nerve injury triggers BRAF to move from peripheral nerves into the spinal cord. 

Nevertheless, this research points to BRAF signalling as a potential therapeutic target for neuropathic pain and suggest that existing BRAF inhibitors could eventually provide a new treatment option for patients living with chronic nerve damage.