Pain that persists in clear skin, in healthy-looking tissue
For the roughly one in 3,000 people living with neurofibromatosis type 1, chronic pain has long been a shadow without a clear source — present even where tumors are not, defying the explanations medicine had to offer. Researchers at Cincinnati Children's have now traced that shadow to its origin: Schwann cells, the nervous system's own support structures, malfunctioning in ways that flood pain-sensing fibers with an amplifying protein called GDNF. The discovery, published in May 2026, not only reframes how NF1 pain is understood but points toward a drug already in use that may quiet those signals at their source.
- Chronic pain in NF1 has resisted explanation for years because it strikes even where no tumors exist — leaving patients suffering and clinicians without a clear target.
- The culprit now identified is GDNF, a protein overproduced by malfunctioning Schwann cells that essentially rewires pain-sensing nerves into hypersensitive alarm systems.
- Mirdametinib, already approved for NF1-related tumors, reduced GDNF levels and measurably calmed pain responses in mouse models by blocking the abnormal signaling pathway driving overproduction.
- The mechanism also explains why pain can precede tumor development and spread across the body in patterns that don't map to visible growths — a long-standing clinical puzzle now partially solved.
- Human trials remain the necessary next step, but a viable drug already exists, and the pathway toward earlier, targeted pain intervention is now visible for the first time.
A team at Cincinnati Children's has answered a question that has long troubled both patients and clinicians: why do people with neurofibromatosis type 1 so often suffer from pain that has nothing to do with their tumors? The answer, published in Science Signaling in May 2026, lies in the behavior of Schwann cells — the cells that insulate and support nerve fibers. When these cells malfunction in NF1, they overproduce a protein called GDNF, which attaches to pain-sensing nerve fibers and turns them into hypersensitive alarm systems. A light touch becomes unbearable. Normal sensation becomes pain.
NF1 affects roughly one in 3,000 people and is widely known for the tumors it produces along nerve pathways. But the disease carries a broader burden — skin markings, learning difficulties, skeletal problems, and a persistent, widespread pain that many patients describe as their most disabling symptom. That non-tumor pain, appearing in tissue that looks healthy and in regions far from any visible growth, has remained poorly understood and difficult to treat.
Led by Michael P. Jankowski and first author Namrata G. R. Raut, the Cincinnati team studied mice engineered to lack the NF1 gene in their Schwann cells. Those cells became overproducers of GDNF, and the mice displayed pain-like responses consistent with what NF1 patients report. When the researchers administered mirdametinib — a MEK inhibitor already approved for NF1 tumors — GDNF levels fell and pain responses diminished. The drug works by blocking the MAPK signaling pathway that drives the overproduction.
The finding reframes NF1 pain in a clinically meaningful way: it explains why pain can appear before tumors do and why it spreads in patterns that don't correspond to visible growths. Human trials will be needed to confirm the mechanism and establish safety, but a drug that might address it already exists. For patients who have lived with pain that medicine could not fully explain, that is a meaningful step forward.
A team at Cincinnati Children's has traced the source of a stubborn mystery: why people living with neurofibromatosis type 1 suffer from chronic pain that often has nothing to do with tumors. The answer, published in Science Signaling on May 26, 2026, points to a protein called GDNF being overproduced by Schwann cells—the cells that normally insulate and support nerve fibers. When those cells malfunction, they flood the nervous system with this pain-amplifying protein, turning up the volume on pain signals even in parts of the body where no tumors exist.
Neurofibromatosis type 1 is a genetic condition that strikes roughly one in every 3,000 people. Most know it for the tumors it causes along nerve pathways, but the disease brings a wider constellation of problems: café-au-lait spots on the skin, learning difficulties, skeletal abnormalities, and the relentless pain that many patients describe as their most disabling symptom. Doctors have long understood tumor-related pain. The non-tumor pain—the kind that persists in clear skin, in healthy-looking tissue—has remained largely a puzzle, difficult to explain and harder still to treat.
The Cincinnati team, led by corresponding author Michael P. Jankowski and first author Namrata G. R. Raut, approached the problem by studying mice engineered to lack the NF1 gene specifically in their Schwann cells. What they found was that these malfunctioning cells became factories for excess GDNF. The protein then attached itself to receptors on pain-sensing nerve fibers, essentially turning those fibers into hypersensitive alarm systems. A light touch became unbearable. Normal sensation became pain.
But the discovery pointed toward a potential fix. The researchers tested mirdametinib, a drug already approved for treating certain NF1-related tumors. It works by blocking a signaling pathway called MAPK. When they used it in their mouse models, something promising happened: GDNF levels in the Schwann cells dropped, and the mice's pain-like responses diminished. The drug, in other words, seemed to quiet the overactive pain signals at their source.
This finding builds on earlier research showing that Schwann cells play a central role in NF1 pain, but it goes further by identifying the specific protein and the specific mechanism. It explains why pain can appear before tumors do, and why it can spread across the body in ways that don't match the location of visible growths. For the roughly one in 3,000 people living with NF1, the implications are significant: if the same mechanism holds true in humans, and if mirdametinib proves safe for this use, doctors might be able to intervene earlier, reducing suffering and restoring some measure of normal function to daily life.
The work is not yet complete. Human trials will be needed to confirm that the mechanism operates the same way in people, and that blocking MAPK signaling can safely relieve pain without unintended consequences. But the pathway is now visible, and a drug that might travel it already exists. The next phase of work will determine whether this laboratory finding can become a clinical reality.
Citas Notables
Pain in NF1 may begin before tumors appear and may be driven by abnormal signaling from Schwann cells producing excess GDNF— Cincinnati Children's research team
Blocking MAPK signaling with a MEK inhibitor lowered GDNF levels in Schwann cells and reduced pain-like responses in mice— Michael P. Jankowski, PhD, corresponding author
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So the pain in NF1 isn't coming from the tumors themselves?
Not always, and not even at first. That's what makes this so important. People report pain in areas where there are no tumors at all. The researchers found that the Schwann cells—the support cells around nerves—are misbehaving and pumping out too much of a protein called GDNF.
And GDNF does what, exactly?
It amplifies pain signals. Think of it like turning up the volume on a speaker. The nerve fibers that sense pain have receptors for this protein, and when GDNF binds to them, they become hyperactive. A normal sensation gets interpreted as pain.
Why would Schwann cells start doing that in NF1?
Because the NF1 gene itself is mutated or missing in these cells. That gene normally acts as a brake on a signaling pathway. Without it, the pathway runs wild, and one consequence is overproduction of GDNF.
And they found a way to stop it?
They tested mirdametinib, a drug already used for NF1 tumors. It blocks the runaway signaling pathway. In mice, it lowered GDNF levels and reduced pain responses.
But will it work in people?
That's the crucial question. The mechanism is clear in mice, but human biology is more complex. They need clinical trials to know if it's safe and effective in actual patients.
What changes if it does work?
Everything, potentially. Right now, NF1 pain is hard to treat because doctors didn't understand where it was coming from. If they can block GDNF safely, they might be able to intervene before tumors even appear, giving people their lives back.