For the past century, the prevailing view among neuroscience researchers has been that nerve endings in the skin are “free” or “bare.” The idea is that these nerve endings, which detect painful stimuli like the prick of a pin or high heat, are off on their own, unencumbered by other kinds of cells.
But an important new study in mice now shows that free nerve endings aren’t so free after all.
The paradigm-challenging research, led by Patrik Ernfors at the Karolinska Institute in Stockholm, Sweden, shows that these nerve endings are ensheathed by a novel type of support cell, at the border between the outer and inner layers of the skin (the epidermis and dermis, respectively).
The discovery of these cells, which the researchers call nociceptive Schwann cells, was unexpected. But even more surprising was the finding that they participated in pain processing by the nervous system.
The study has far-reaching implications for how scientists understand the pain system, and perhaps for the treatment of pain, too.
The study is “superb work, which is what these authors do, and puts forth an exciting finding,” said Frank Rice. Rice is a histologist and pain researcher at Integrated Tissue Dynamics, a company in upstate New York, but was not involved in the new research.
The findings appeared August 16, 2019, in the journal Science.
Visualizing a new kind of glial cell
Schwann cells are a subtype of a class of cells called glial cells. Glial cells provide neurons with multiple forms of support in the central nervous system (brain and spinal cord) and in peripheral nerves.
In the case of Schwann cells, they typically wrap around peripheral nerves, forming a substance called myelin that insulates the nerves and allows them to send faster electrical signals.
Ernfors’s group has long used genetic techniques in mice to study the precursors to Schwann cells. These precursors have characteristics of stem cells, which can mature into a variety of cell types.
“We use mouse genetic tools to look at all the cell types derived from these precursors,” Ernfors said, which led him to the nociceptive Schwann cells. “We found that these glial cells are numerous and form a web-like mesh in the dermis, with radial processes that follow the nerve into the epidermis.”
“It’s a cool idea; they are on to something very important,” said Cheryl Stucky, a pain researcher at Medical College of Wisconsin in Milwaukee, who was not involved in the new study.
More than innocent bystanders
The researchers then turned to a technology called optogenetics, which uses light-sensitive proteins to turn the activity of different types of cells on or off. Here, they used mice genetically engineered to contain one of those light-sensitive proteins but only in the nociceptive Schwann cells, and in no others.
Remarkably, when the scientists shined blue light on the hind paws of these mice to activate the cells, the animals withdrew their paws. They also shook and licked their paws, something mice do to “cope” with pain.
And, the higher the light intensity, the more the mice showed these behaviors. This indicated that the activity of the nociceptive Schwann cells was driving the behaviors.
Laura Calvo-Enrique, one of the study authors, said that when she first heard that the light caused these responses, she found it hard to believe, because glial cells were not expected to participate in pain signaling.
“I thought, Am I missing something? But the first time I saw the animal withdraw its paw from the blue light, it was like, Wow! This is really true.”
More experiments would show that the newly-discovered cells were most important for detecting mechanical stimuli, in this case a poke to the paw (a common test used by pain researchers to understand the pain system in animals).
A game changer
Interestingly, the existence of Schwann cells like those identified in the current study had actually been documented previously by Rice and others.
“Even ten years ago, we saw these cells, but we couldn’t make any sense of them, other than they were kind of interesting. We had no physiological data or evidence that they were functionally interacting with the nerve terminals,” Rice said.
But the first documentation of the Schwann cells that Ernfors found dates to 1973. The author of that older study “described a cell that looked like an octopus in the skin,” Ernfors said.
However, although the Schwann cells had been spotted before, Rice said, “they were not part of the thought process” when it comes to studying the pain system. But new techniques like optogenetics have a way of pushing knowledge forward.
“When you have the right tools, suddenly the pieces start coming together. And now we have evidence that these cells are important players in pain mechanisms—it’s going to be a game changer,” Rice said.
So the idea of free nerve endings in the skin needs an update: it’s not only neurons that matter there, but different cells types too, in this case the Schwann cells.
A role in chronic pain?
The new findings are not only a game changer for a basic understanding of how the pain system works. They also have big-time implications for the understanding of chronic pain in people.
“Of course we are very interested in their role in chronic pain,” Ernfors said of the nociceptive Schwann cells. That’s because in small-fiber peripheral neuropathy, a pain condition resulting from damage to nerve fibers, “free” nerve endings in the epidermis retract.
“With this close association of the glia cells to nerves, it obviously raises the question of what role they play in chronic pain. We don’t have the answer, but we are studying that,” Ernfors continued.
Rice said that a major focus in pain research is to understand why peripheral nerves are hyperactive in the setting of chronic pain. The new findings suggest that “maybe it’s what’s talking to the nerves that is important,” referring to the nociceptive Schwann cells.
“What happens to nociceptive Schwann cells in their function, structure, and communication after nerve injury, tissue injury, or peripheral disease?” Stucky later wrote in an email. “If changes occur, how they contribute to persistent pain, itch, or touch hypersensitivity will be very interesting to discover.”
This story is a plain language translation of a story that first appeared on the IASP Pain Research Forum.
Stephani Sutherland, PhD, is a neuroscientist and freelance journalist in Southern California. Follow her on Twitter @SutherlandPhD