Surprisingly, scientists haven’t found all the types of neurons that send pain signals. Without knowing all the pieces to the puzzle, it’s challenging to make sense of things when these cells malfunction, as is the case with chronic pain.
But now, using recently developed techniques that allow scientists to watch hundreds to thousands of neurons active at once in live mice, a team of researchers at the National Institutes of Health in Bethesda, US, discover a new kind of pain-sensing neuron: one that’s responsible for the painful sensation experienced when pulling on even just a single hair.
They also find that these neurons wrap around hair follicles like lassos deep within the skin. Ultimately, the cells could play a role in chronic pain in people, though that has yet to be tested.
“It’s a really interesting study,” says Cheryl Stucky, Medical College of Wisconsin, Milwaukee, US, a pain researcher who was not involved in the new work. “As any person can tell you, it’s very painful to have your eyebrows plucked one hair at a time.”
The work was published online August 16 in the journal Neuron.
How we feel: it’s complicated
How people feel the outside world, whether a cool breeze, a painful bee sting, or the warmth of a fire, is an intricate process involving many different types of nerve cells.
“How do you depict the chaotic gentle swirl of a summer breeze?” asks Alexander Chesler, who led the study.
To transmit that complex signal, specialized neurons must be able to detect different aspects of the breeze such as temperature and force. “It’s an incredibly rich signal,” explains Chesler.
Pain-sensing neurons have been especially hard to understand for just this reason, as there are many different forms of pain, each of which depend upon specific neurons. For example, some neurons detect burning heat while others detect the sharp mechanical pain from a needle.
Given the sheer number of ways to experience pain, it’s no wonder that researchers have struggled to identify and categorize all the neurons responsible for pain sensation. This is particularly true for the cells that control the response to painful mechanical stimuli, a process known as mechanosensation.
But with the recent development of some very powerful techniques in the field of neuroscience, Chesler and his team thought the time was ripe for new advances.
Green flashes light the way
So the researchers turned to a technique called calcium imaging. This approach uses a genetic manipulation to insert a fluorescent protein into neurons of live mice.
The protein flashes green whenever it comes in contact with calcium, which rushes into the cell when a neuron is activated. Calcium imaging allows scientists to monitor clusters of neurons under a microscope, waiting for flashes of green that indicate which cells are activated at a given time.
Instead of putting the protein into all neurons, the team instead placed it into a specific population of pain-sensing neurons. They then anesthetized the mice and stimulated their cheeks with a series of stimuli such as gentle stroking, painful heat or cold, or the painful pulling of whiskers. Upon doing so, they monitored a cluster of neurons that sit at the base of the skull; these neurons are known to detect sensory stimuli applied to the face.
Like stars flickering in the night sky, a symphony of neurons flashed green in response to painful hair pulling, painful heat, or both.
A new type of neuron
Chesler thought it was fascinating that these cells responded to painful hair pulling—even to pulling of just a single hair. This was because the only neurons responsive to hair stimulation in previous studies were touch-sensitive neurons—not pain-sensitive ones—responsible for the sensation of gentle movement of hair.
To get a better look, Chesler used a chemical technique to kill off all the heat-sensitive neurons. This left behind only those that were sensitive to hair pulling, allowing the researchers to focus specifically on those cells.
Using an imaging technique to visualize the anatomy of these neurons within the skin, the group found that they wrapped in circles around individual hair follicles. Because of this interesting anatomy, and because the cells became activated by high-intensity pulling of hair, the researchers named the neurons “Circumferential High-Threshold Mechanical Receptors” or Circ-HTMRs for short.
What does it all mean for chronic pain?
Circ-HTMRs may play a role in chronic pain, especially with regard to allodynia, a characteristic feature of many pain conditions. Here, normally harmless stimuli, such as the brush of a feather across the skin, cause excruciating pain.
“We know that some patients develop allodynia, but it doesn’t really occur in the glabrous [hairless] skin, such as your palms. Instead, it happens in the hairy skin,” explained Stucky. Thus, the newly identified pain neurons may play a role in this common clinical problem.
Although the new findings won’t immediately lead to new treatments for chronic pain, Chesler believes they could ultimately have a big payoff.
“The goal is to help with something that is very important medically,” explains Chesler. But “to do that, a deep understanding of these neural mechanisms is essential.”
To read about the research in more detail, see the related IASP Pain Research Forum news story here.
Nathan T. Fried is a postdoctoral fellow at the University of Pennsylvania, Philadelphia, US.