Mutations in People Who Can’t Sweat or Feel Pain May Suggest Drug Targets for Chronic Pain

A study that examined gene mutations in people with a rare condition that stops them sweating or feeling pain could point the way towards identifying new drug targets for people suffering from chronic pain.

Chronic pain and the opioid crisis

Chronic pain affects 50 million adults in the United States, and efforts to manage the crisis have had disastrous consequences. The opioid crisis, which has plagued the US for over two decades, began with the marketing of addictive opioid pain relief drugs as non-addictive. Clinicians, in efforts to help their stricken patients, enthusiastically prescribed these medications, leading to an epidemic of addiction that landed Purdue Pharma, who knew their opioid drug OxyContin was addictive but pretended otherwise in its marketing, with a $365 million fine. New, non-addictive compounds to treat pain are desperately needed. “Chronic pain is a global public health problem,” Deborah Schechtman, assistant professor at the University of São Paulo and the study’s senior author, told Technology Networks.

An incredibly rare condition

Schechtman and her team examined genetic data from 231 patients with an exceedingly rare condition known as congenital insensitivity to pain with anhidrosis (CIPA). Roughly 1 in 125 million people are affected by CIPA, which causes a loss of algesia (the ability to feel pain), the inability to sweat and can also produce wider symptoms such as developmental delay and intellectual disability.

CIPA is caused by mutations in a gene called NTRK1, which encodes an important receptor in the brain, tropomyosin receptor kinase A (TrkA). TrkA is activated by a molecule called nerve growth factor (NGF), which, during the brain’s development, leads to the formation of pain-sensing neurons.

In the mature brain, NGF and TrkA signaling contribute to inflammation and nerve pain. The impact of CIPA on this pathway made the patients’ gene data an obvious target for the group. “Mutations in TrkA may abolish NGF signaling completely and patients with these mutations don´t feel pain. Learning how the different mutations affect pain signaling pathways may help identify new targets and develop new drug leads,” explained Schectman.

Previous studies in mice that tried to widely dampen signaling through TrKA or NGF hit barriers, Schechtman says: “Abolishing [...] NGF signaling may affect neuron remodeling, producing unwanted side effects. Specifically identifying pathways mediated by NGF that lead to pain and do not affect neuron remodeling and inhibit these pathways may reduce side effects.”

Mapping mutations

To examine the exact mutations that might be responsible for halting pain, the team mapped the CIPA patients’ genetic data onto a simulated 3D model of TrkA. The team identified a total of 467 mutations across the NTRK1 gene. They noted that many of those mutations affected a region called the kinase domain, which plays a role in speeding up chemical reactions involving the receptor.

Based on previous evidence, Schechtman and team knew that an enzyme called phospholipase-gamma (PLCγ) may play a role in TrkA pain signaling. They noted that many of the mutations in CIPA patients interrupted the binding between TrkA’s kinase domain and PLCγ.

Mimics disrupt a pain pathway

The team decided to employ some subterfuge to perform their own disruption to the pain pathway. They created a mimic that could trick PLCγ into binding with it instead of TrkA, reducing the amount of pain signaling through this molecule.

The researchers showed that their decoy molecule, TAT-pQYP, worked as intended in human embryonic kidney cells and then went on to demonstrate that mice injected with the molecule showed reduced sensitivity to inflammatory pain.

The authors are cautious about their findings – the pathways being analyzed are complex and can often have many roles in different biochemical processes that may cause unexpected side effects. But Schechtman is clear about the need to continue such research to find solutions for chronic pain sufferers. “Around 50% of these patients are refractory to all available drugs. Understanding more about pain pathways can help to identify new targets and to develop new therapeutic drugs,” she concluded.

Reference: Moraes BC, Ribeiro-Filho HV, Roldão AP et al. Structural analysis of TrkA mutations in patients with congenital insensitivity to pain reveals PLCγ as an analgesic drug target. Sci. Signal. 2022; 15. doi: 10.1126/scisignal.abm6046