Our senses, touch and pain have helped us survive the many environmental conditions we face, in addition to the other senses. We can easily distinguish the scorching heat on a sunny afternoon and the warmth of a blanket or the softness of a towel from the roughness of sandpaper. When we eat, we can quickly tell a pungent taste apart from a mild or bland one. The ability to sense our surroundings and react accordingly is vital for our safety and survival. However, people with neurological conditions such as stroke, diabetic neuropathy, or any condition with peripheral nerve damage may lose the ability to perceive pain and touch— a condition that could be life-threatening.

For a long time, scientists have been trying to understand how exactly we perceive impulses from the environment. Our body consists of sensory nerve fibers that perceive stimuli and transfer them first to the spinal cord and then to the brain. By the 20th century, it was known that sensory nerve fibers react differently to temperature and pressure. However, the molecular basis for our perception of temperature, touch, and pressure remained undiscovered.

Working towards this problem, David Julius, Professor and Chair, Dept. Of Physiology, University of California, San Francisco, discovered receptors in sensory neurons that are activated by noxious heat, pain, cold, and certain chemicals. Ardem Patapoutian, Professor, Howard Hughes Medical Institute, discovered the ion channels that play a crucial role in sensing mechanical stimuli such as touch and pressure. Julius and Patapoutian jointly received the 2021 Nobel Prize in Physiology or Medicine “for their discoveries of receptors for temperature and touch.”

David Julius was the speaker of the 2024 TNQ Distinguished Lectures and presented his talk on How we sense pain.

For their research, Julius’ group used stimulants from nature— such as capsaicin, a substance from chili peppers. The burning sensation and sweating after eating even a small bit of red-hot chilies is caused by capsaicin.

Julius’ group used capsaicin to identify proteins in the sensory neurons that sensed noxious heat. Through their experiments using sensory neurons from rodents, they identified the gene encoding for the protein TRPV1 (pronounced as trip-V-1), an ion channel that responds to heat from capsaicin. TRPV1 is also activated at temperatures above 43°C (110°F). TRPV stands for transient receptor potential vanilloid.

Fun fact: Birds such as parrots also have vanilloid receptors in their sensory neurons, but capsaicin cannot activate them. Thus, birds can consume chili peppers without experiencing any adverse reaction and help in the dispersal of seeds.

Julius’ group also characterised the gene TRPA1, a detector of pungent chemicals including those from garlic and mustard, and harmful chemicals in the environment.
Additionally, Julius and Patapoutian independently discovered TRPM8, the receptor activated by cold, using menthol as a natural compound. TRPV1, TRPA1, and TRPM8 are all members of the TRP family of receptors. In addition, several other TRPs are present and distributed all over the body in different organs.

While Julius’ work identified the different TRP receptors,  Patapoutian’s group worked on identifying PIEZO1 and PIEZO2— the ion channels that enable our detection of touch and pressure. The PIEZO receptors are large proteins, each consisting of 2500 amino acids and 38 transmembrane helices. The PIEZO channels are expressed in several tissues and organs, including the excretory, intestinal, and cardiovascular systems, among others.

Targeting TRP receptors for pain treatment

Capsaicin has been in use as a classic agonist of TRPV1 for treating pain. An agonist is a substance that binds to and activates the receptor. Capsaicin reduces pain by desensitising the TRPV1 receptor. It is mainly used to treat neuropathic pain, i.e., pain due to damage to the nervous system. In addition to capsaicin, resiniferatoxin (RTX) is also used as a TRPV1 agonist. On the other hand, there are TRPV1 antagonists that block the receptor and inhibit the perception of pain. Mavatrep is a TRPV1 antagonist with promising effects in treating osteoarthritic pain. Agonists and antagonists of TRPA1 and TRPM8 are also being tested in clinical trials as candidates for pain management.

Research on the TRP and the PIEZO channels has significantly advanced our understanding of pain, temperature and mechanical force. It has opened new avenues for further investigating our perception of environmental stimuli, elucidating the cause of pain, and developing treatments for various conditions such as arthritis, migraine, asthma, inflammatory bowel syndrome, or chemotherapy-induced neuropathy.