Molecular Clues Reveal Why Neuromas Cause Pain

Peripheral nerves are built to repair themselves. After an injury, axons—the long, signal-carrying extensions of nerve cells—can grow outward in search of their original targets, guided by chemical signals and structural pathways in surrounding tissue. When that journey succeeds, sensation and movement may gradually return. But when a regenerating nerve cannot reconnect with its target, the growing axons may become tangled into a disorganized mass known as a neuroma. In many patients, these growths are intensely painful, particularly after traumatic injuries, surgical procedures, or limb amputations.

A new study published in PNAS Nexus suggests that painful neuromas are not simply bundles of misdirected nerve fibers. Instead, their axons appear to undergo a distinct molecular transformation that makes them unusually excitable and responsive to mechanical stimulation. Kyle Eberlin and colleagues examined the molecular architecture of ten painful neuromas removed during surgery and compared them with six healthy peripheral nerves obtained from lower-leg amputations performed for unrelated medical reasons. The comparison revealed a sharp shift in the identity and behavior of the nerve fibers inside the neuromas.

The researchers used immunofluorescent confocal microscopy, a technique that allows specific proteins and cellular structures to be labeled with fluorescent molecular markers and visualized in three dimensions. Neuroma and healthy-nerve samples were processed into sections 50 micrometers thick before staining. This approach enabled the team to map proteins associated with axonal regeneration, pain signaling, mechanical sensation, electrical excitability, and sympathetic innervation—the network of nerves involved in involuntary functions such as blood-vessel control.

Under the microscope, the axons within painful neuromas lacked the orderly organization seen in healthy nerves. Rather than running in aligned bundles toward a defined destination, the regenerating fibers formed irregular, densely packed structures. They also displayed high levels of markers associated with active growth and repair, indicating that the axons remained in a regenerative state even though they had failed to establish a functional connection with their target tissue.

One of the most striking findings involved calcitonin gene-related peptide, or CGRP. This neuropeptide is released by sensory neurons and plays a major role in transmitting and amplifying pain. CGRP can also contribute to inflammation and heightened sensitivity in injured tissues. In the neuroma samples, 84 percent of axons expressed CGRP, compared with only 3 percent of axons in healthy nerves. The difference suggests that a large proportion of the fibers in painful neuromas may be molecularly primed to detect and transmit nociceptive signals—the signals the nervous system interprets as potentially damaging or painful.

The neuromas also showed increased expression of Piezo2, a mechanically activated ion channel. Piezo2 opens when the cell membrane is deformed, allowing positively charged ions to enter the nerve cell and initiate electrical activity. In normal sensory neurons, this mechanism helps detect light touch, pressure, vibration, and body position. Within a disorganized neuroma, however, mechanical forces such as contact, stretching, or pressure may activate abnormal axonal endings. This could explain why even minor pressure against a scar or amputation site can trigger severe, shock-like pain.

Another important marker was Nav1.3, a voltage-gated sodium channel involved in the initiation and propagation of electrical impulses. Sodium channels are essential for nerve signaling, but their expression changes after injury. Elevated Nav1.3 can make damaged neurons more likely to fire spontaneously or respond excessively to weak stimuli. The researchers found that Nav1.3 was upregulated in the neuromas, adding another molecular indication that these nerve fibers had become hyperexcitable. Together, increased CGRP, Piezo2, and Nav1.3 point to a nerve structure simultaneously tuned for pain detection, mechanical sensitivity, and rapid electrical activation.

The study also identified an abundance of sympathetic nerve fibers within the painful neuromas. Sympathetic nerves are not traditionally considered the primary conductors of pain, yet growing evidence indicates that they can interact with injured sensory fibers and influence chronic pain. Chemical communication between sympathetic and sensory neurons may intensify inflammation or promote spontaneous activity in damaged axons. Their presence in the neuromas raises the possibility that the local nerve environment, rather than the sensory axons alone, contributes to persistent pain after nerve injury.

The findings may help explain why painful neuromas are difficult to treat and why conventional pain medicines do not always provide lasting relief. Current surgical approaches attempt to remove the abnormal tissue or redirect regenerating axons into muscle, bone, or other protective targets. The molecular profile described in this study suggests additional possibilities, including therapies designed to reduce CGRP signaling, inhibit abnormal Piezo2-mediated mechanosensation, or normalize Nav1.3 activity. Treatments that disrupt interactions between sympathetic and sensory fibers could represent another avenue. These possibilities remain experimental, and the study does not establish that any single marker causes neuroma pain.

The researchers emphasize that their work is based on a relatively small collection of human specimens, and the comparison between amputated nerves and surgically removed neuromas cannot capture every biological difference between patients. Nevertheless, studying human tissue directly provides a valuable view of the condition that animal models may not fully reproduce. Axonal regeneration is widespread across the animal kingdom, but the formation of painful neuromas appears to be a comparatively recent evolutionary development, emerging in birds and mammals. Understanding why regeneration becomes maladaptive in these species may ultimately reveal how healing turns into chronic pain—and how that process can be interrupted.

News Publication Date: 11-Aug-2026

Web References: https://mediasvc.eurekalert.org/Api/v1/Multimedia/ffe0045b-cc00-42e9-ad96-94911df62e49/Rendition/low-res/Content/Public

References: PNAS Nexus, “Painful neuromas exhibit axonal phenotypic shift via nociceptive and mechanosensitive marker up-regulation.”