There’s So Much More To Explain About How Bodies Sense Pain

(Inside Science) -- This year’s Nobel Prize in physiology or medicine went to two scientists who discovered how our sense of temperature and touch works. David Julius identified the heat-sensing ion channel TRPV1, while Ardem Patapoutian found the touch-sensitive Piezo channels.

Both channels form pores in cell membranes, which allows the cells to send electrochemical signals through the body. That process is involved in how our bodies sense pain -- from heat and from mechanical force, respectively. But pain is a much more complicated phenomenon than can be captured by simple biochemical pathways. The molecular channels identified by the Nobel winners are just the beginning of that story, and there is much more left to be discovered, especially about how the pain signals provided by those channels are transmitted to and interpreted by the brain.

“Pain is a very complex effect,” said Serge Marchand, a pain researcher at the University of Sherbrooke in Quebec. “There are still a lot of things we don’t understand.”

For pain from heat, at least, things are easier to understand. The TRPV1 channel is the only starting point needed to get the sensation of heat from the skin to the brain. Mice that lack the gene to produce TRPV1, or whose neurons that contain the ion channel have been killed off, are unable to feel heat pain -- though the site of a burn is still sensitive to pain from mechanical stimulation afterwards, said Allan Basbaum, a pain researcher at the University of California, San Francisco who worked on the mouse studies with Julius.

With pain from pressure and touch, however, things are more complicated. The Piezo channels are responsible for the pain you feel when something touches skin made sensitive by, for example, a bruise, but they are not involved in acute mechanical pain, such as the type you feel when you hit your thumb with a hammer.

“We don’t have a single channel that is necessary for the experience of acute mechanical pain,” said Basbaum. “There isn’t one you can block to prevent the sensation, as with heat and TRPV1.” In fact, we don’t actually know what biochemical pathways detect that sensation and send that signal to your brain.

The signals of acute mechanical pain could be integrative, said Basbaum, with multiple pathways generating input that eventually crosses some threshold where the brain identifies it as pain. That question of when the brain recognizes a sensation as pain is one of the field’s biggest mysteries.

“Pain is a product of the brain. It is an emotional response,” said Basbaum. “The brain reads the output of a pattern of nerve activity and makes a decision.” That decision is the difference between, for example, whether something is felt as an irritating itch or excruciating pain.

Marchand is most interested in how the brain makes those decisions in response to the messages it receives from nerves outside the central nervous system of the spine and brain. The processing of these messages and decisions can go awry, including in people with the condition known as allodynia, in which even a gentle touch can be extremely painful, and in people who feel phantom pain after the amputation of a limb.

Even if we had a perfect understanding of how the receptors and nerves extending from the surface of the skin to the spinal cord work, that still wouldn’t explain all of the unknowns of pain.

“If phantom pain can exist, it means that in the central nervous system there is enough wiring to reproduce a painful sensation in the fingers even if there are no fingers,” Marchand said. A better understanding of these phenomena would lead to better treatments for patients and could help explain why some people are more prone to chronic pain than others, he said.

Basbaum said one of the biggest outstanding questions about pain is the search for some kind of biomarker that would help researchers and doctors detect and quantify pain with a simple blood test or brain scan. Some researchers are looking at whether the levels of inflammation-regulating cytokines in the blood correlate with pain levels and change with the use of painkillers, for example. But the complexities of the interactions between the physical aspects of an injury, the signals sent by the nerves, and the interpretation of those signals by the brain make that search very difficult, he said. “Pain is not just a function of the intensity of a stimulus,” he said. “It’s influenced by so many things, like your emotional state and the context of the experience. It doesn’t produce the same effect in everybody.”

For more of Inside Science’s coverage of the 2021 Nobel Prizes in physiology or medicine, physics and chemistry, please visit our Nobel coverage page .