TRPV1 Sensory Neuron Mutations Found to Influence Pain Perception

A recent study from the Butantan Institute’s Special Pain and Signaling Laboratory (LEDS) in São Paulo, Brazil, in partnership with several other universities, discovered a potential pain insensitivity mutation in the TRPV1 gene, a sensory neuron receptor. TRPV1 is a receptor that senses noxious stimuli, and the team found that the mutation K710N in the gene encoding this protein could be used as a potential painkiller. The study also showed that the mutation could protect against other stimuli, such as cellular stress, tissue ischemia, and neurogenic inflammation.

Initially, researchers used a computational approach to compare the genetic sequences of avian and human TRPV1 to identify five avian mutations believed to be linked to pain resistance. Cryogenic electron microscopy helped determine that the five avian mutations were located in the amino acid residue K710, which controls gating of the TRPV1 channel. Though the mutations can also be present in humans, they’re infrequent. 

The team transplanted these variants into genetically modified cells to test the function of the channel. After they saw that the channel’s function was altered, they utilized CRISPR/Cas9 to create mice with the mutation K710N, which reduced the receptor’s reaction to capsaicin in cells.

When the scientists injected the mice with the K710N mutation with capsaicin and gave them peppery chicken feed, they did not observe nociceptive behavior (suggesting avoidance of pain), unlike normal mice, which lifted their paws to avoid touching the capsaicin, presumably because even skin contact caused pain.

The K710N mutation mice also showed less hypersensitivity to nerve injury, while their response to noxious heat remained intact. Moreover, blocking the K710 region in normal mice limited acute behavioral responses to noxious stimuli and returned pain hypersensitivity induced by nerve injury to baseline levels.

In the second part of the study, researchers attempted to reduce the receptor’s function pharmacologically. They developed a peptide, V1-cal, which acted selectively on the K710 region. Mice treated with V1-cal and given capsaicin displayed less nociceptive behavior and diminished release of neuropeptides leading to inflammation and edema without altering temperature. Lastly, chronic pain also improved considerably.

The researchers want to validate their results under best-practice laboratory conditions, identify other small molecules besides the peptide that can more easily be synthesized, conduct preclinical trials, and begin a clinical trial if these are successful. The study provides promising results that the K710N mutation in the TRPV1 gene can potentially limit the pain response, opening future avenues of investigation for pain researchers.