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Pain Nerve Endings: “Bare” No More

Nociceptive Schwann cells in the skin are an active player in pain sensation

by Stephani Sutherland


14 October 2019


PRF News

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Nociceptive Schwann cells in the skin are an active player in pain sensation

For the past century, dogma has held that unmyelinated nociceptive sensory neurons have “bare” or “free” nerve endings that extend into the epidermis where they detect harmful stimuli directly, unencumbered by end-organ cells. But a new study in mice led by Patrik Ernfors, Karolinska Institute, Stockholm, Sweden, shows that nociceptive nerve endings are ensheathed by a novel type of glial cell, which the authors call nociceptive Schwann cells.

 

The Schwann cells form a mesh-like sensory organ at the border between the epidermis and dermis, where they wrap around nerve endings. But even more surprising is the finding that the cells participated in detecting mechanical and thermal nociceptive stimuli. The study has far-reaching implications for pain physiology, and perhaps for the treatment of chronic neuropathic pain.

 

The study is “superb work, which is what these authors do, and puts forth an exciting finding,” said Frank Rice, a histologist and pain researcher at Integrated Tissue Dynamics, Rensselaer, New York, US, who was not involved in the research.

 

“The long-standing belief has been that nociception is an axonally driven process, with perception occurring in the most distal nerve endings, which were previously thought to be free of any glial ensheathment,” write Ryan Doan and Kelly Monk, Oregon Health & Science University, Portland, US, in a perspective accompanying the new paper. “The discovery … of nociceptive Schwann cells that cross the basement membrane into the epidermis, where they form a mesh-like nociceptive network with the axonal field, changes this view and provides a new potential target cell for pain medication,” they write.

 

The paper and accompanying perspective were published August 16, 2019, in Science.

 

Visualizing a new kind of glial cell

To identify nociceptive Schwann cells in the skin, the team used a genetic cell-lineage tracing technique that identifies mature and differentiated cells based on their cellular origin. Ernfors has long been studying stem-like Schwann precursor cells, which can be fluorescently labeled by their expression of the genes Plp1 and Sox10.

 

“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.”

 

Immunohistochemistry showed that the Schwann cells associated with nerve fibers that expressed calcitonin gene-related peptide (CGRP), the ATP receptor P2X3, and transient receptor potential vanilloid 1 (TRPV1) channels. Collagen fibers supported the neuro-glial complexes.

 

“It’s a cool idea; they are onto something very important,” said Cheryl Stucky, a pain researcher at Medical College of Wisconsin, Milwaukee, US, who was not involved in the new study. “The imaging data are beautiful.” Stucky added, “This finding may change the way we view ‘free nerve endings’—they may not actually be ‘free,’ as has been taught in textbooks for the past 50 years.”

 

Nociceptive Schwann cell activity triggers withdrawal behavior

The researchers then employed optogenetics to selectively activate the nociceptive Schwann cells by crossing the driver lines of mice with the excitatory light-sensitive protein channelrhodopsin 2 (ChR2), creating Sox10-ChR2 mice and Plp-ChR2 mice. Remarkably, when they shined blue light on the hind paw of mice with ChR2 expressed exclusively in the Schwann cells of each strain, the animals withdrew their paws and displayed “coping” behaviors such as paw shaking and licking. Withdrawal and coping responses increased with higher light intensity.

 

Co-first author Laura Calvo-Enrique said that when she joined Ernfors’ laboratory, her fellow co-first author Hind Abdo already had the optogenetic experiments up and running. When Calvo-Enrique heard that light stimulation of glial cells caused nocifensive behaviors, she found it hard to believe. “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.”

 

Extracellular recordings showed that the associated nerves fired in response to the Schwann cell activity. “They communicate in some way with the nerve; we don’t know how. But when they’re excited, the nerve gets excited, and you get nerve conduction,” said Ernfors.

 

“I agree there’s nerve activity,” Stucky said of the nerve recordings, “but it would have been nice to know more than that, such as what types of fibers are firing.”

 

Other sensory neurons that detect light touch and vibration end in specialized structures called end-organs, including Merkel cells and Meissner’s corpuscles, which were first described more than 150 years ago, Ernfors said. “But for pain, everyone always thought that the nerve endings were not associated with any kind of sensory organ—they were always looked at as free nerve endings.” But the new study suggests that nociceptive Schwann cells form an end-organ and play an active role in sensing noxious stimuli.

 

Although C-fiber nociceptors are unmyelinated, they are associated with non-myelinating glia called Remak Schwann cells, which bundle C-fiber axons together into Remak bundles. The nociceptive Schwann cells extend beyond the Remak bundles to ensheath the nerve terminals.

 

A particular modality?

To determine whether the Schwann cells participated directly in sensing noxious stimuli, the team delivered blue light to the animals’ paws at a subthreshold intensity.

 

“We wanted to depolarize the Schwann cells so little that we would not cause any pain behavior, and then combine that slight depolarization with a natural stimulus, like heat or mechanical touch,” Ernfors said. “In this way, we hoped to resolve which modalities the cells participated in detecting.” Mice receiving subthreshold light stimulation displayed increased coping behaviors in response to a mechanical poke, but no change in response to light touch.

 

“They are a highly specialized and mechanosensitive glial cell,” Ernfors said of the nociceptive Schwann cells.

 

Mice also had increased responses to heat and cold stimuli with low-light stimulation. But when nociceptive Schwann cells expressing the inhibitory light-sensitive proton pump archaerhodopsin were silenced with yellow light, mice showed no change in cold responses or heat threshold. Mechanical threshold, however, was significantly increased.

 

“These Schwann cells are sufficient to modify both cold and heat pain. And they are both sufficient and required for mechanical nociception,” Ernfors said. “My interpretation is that the nerve itself is the main component for temperature sensing. But for mechanical stimuli, the Schwann cell is actually really contributing to nociception.”

 

Study co-author Jose Martinez Lopez made electrophysiological recordings from the nociceptive Schwann cells in culture, making him perhaps the first person ever to patch these glial cells. He found that the cells had a resting potential and electrical properties similar to neurons. The cells responded to positive and negative mechanical forces with fast electrical changes.

 

A role for previously recognized but enigmatic cellsfinally!

The existence of Schwann cells like those identified in the current study had actually been documented previously by Rice and others, including in a recent paper in which such cells appeared to play a role in the development of neurofibromas and pain symptoms in the skin of people with neurofibromatosis type I (Rice et al., 2019).

 

“Even 10 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.

 

A 2001 study of metabotropic glutamate receptors at peripheral nerve endings by Robert Gereau and colleagues at Washington University, St. Louis, US, also documented the curious glia in mice (Bhave et al., 2001). “We were fascinated by the appearance of what looked to be synapse-like contacts between these Schwann cell processes and the peripheral nerves,” Gereau wrote to PRF in an email. “We had no way to test the functional implications of this interaction at the time. So I was happy to see this paper from Patrik Ernfors’ group, because it brought these complexes to life for me with these really remarkable findings.”

 

But the first documentation of the Schwann cells that Ernfors found dates to a 1973 electron microscopy study of the skin (Cauna, 1973). The author of that study “described a cell that looked like an octopus in the skin,” Ernfors said. “When many of these cells come together, they form a mesh-like web that is the nociceptive sensory organ.”

 

Although the Schwann cells had been spotted before, Rice said, “they were not part of the thought process” when it comes to studying pain transduction. “We get locked into thinking about more traditional mechanisms. But they did the right experiments,” thanks in part to new technology such as genetic labeling and optogenetics. “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.”

 

“The work buoys the viewpoint that it’s not just neurons that are important for nociception,” Stucky said. “There are other key cell types, and these Schwann cells seem to be part of this complex around the terminal that’s really critical to how the nerve cells respond. It makes a lot of sense that they’re a player.” Recent research from Stucky’s group and others has shown that other non-neuronal cells including keratinocytes can modulate and initiate nociceptive nerve firing (Baumbauer et al., 2015Moehring et al., 2018).

 

A role in chronic pain?

In terms of future work, “Of course we are very interested in their role in chronic pain,” Ernfors said of the nociceptive Schwann cells, because small-fiber peripheral neuropathy is characterized by the retraction of so-called “free” nerve endings in the epidermis.

 

“With this close association of the glial 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 determine why peripheral nerves are hyperactive in chronic pain states. The new work suggests that “maybe it’s what’s talking to the nerves that is important—these terminal glia. That idea is not in the realm that we traditionally think of as pain mechanisms.”

 

“What happens to nociceptive Schwann cells in their function, structure, and communication after nerve injury, tissue injury, or peripheral disease?” Stucky later wrote to PRF in an email. “If changes occur, how they contribute to persistent pain, itch, or touch hypersensitivity will be very interesting to discover.” 

 

Stephani Sutherland, PhD, is a neuroscientist and freelance journalist in Southern California. Follow her on Twitter @SutherlandPhD

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