Study Links TRPV1 Nerve Fibers to Ongoing Burning Pain in Diabetic Neuropathy

In the enduring challenge of managing painful diabetic polyneuropathy, new research is pointing toward a sensory culprit that could explain one of the condition’s most distressing symptoms: ongoing burning pain. A study published in PAIN (April 2025 issue) has identified a strong association between this specific pain phenotype and increased expression of epidermal nerve fibers containing the heat-sensitive channel Transient Receptor Potential Vanilloid 1 (TRPV1).

Led by Dr. Andrea Truini and colleagues at Sapienza University in Rome, the study provides a detailed histopathological look at nerve fiber changes in patients with type 2 diabetes experiencing neuropathic pain. It focused on TRPV1, a receptor well-known for its role in heat perception and inflammatory pain, and famously activated by capsaicin, the compound responsible for chili pepper burn. While TRPV1 has long been implicated in pain pathways in animal models, its direct association with specific pain sensations in human diabetic neuropathy had remained unclear.

In this cross-sectional study of 70 individuals with confirmed diabetic polyneuropathy, researchers used skin biopsies to quantify intraepidermal nerve fiber densities immunostained for TRPV1 and the pan-neuronal marker PGP9.5. Neuropathic pain symptoms were systematically classified using the Neuropathic Pain Symptom Inventory (NPSI). Among the 40 patients with painful polyneuropathy, 70% (n = 28) reported ongoing burning pain—the most frequently cited complaint.

What set these patients apart was a statistically significant increase in TRPV1-positive intraepidermal fibers and a higher TRPV1/PGP9.5 ratio compared to patients with painless neuropathy or other pain subtypes such as electric shocks or squeezing sensations. These findings suggest that the burning quality of pain may reflect not just a subjective descriptor but a pathophysiologically distinct subtype of neuropathy, mediated by increased TRPV1 expression.

The authors interpret these findings as evidence of functional changes in specific nociceptive pathways. Supporting this, the overall density of small fibers, as measured by PGP9.5, did not differ significantly between groups, reinforcing the idea that ongoing burning pain may arise from selective upregulation or sensitization, rather than general fiber loss.

The research also found increased dermal innervation of Calcitonin Gene-Related Peptide (CGRP) fibers, a neuropeptide released downstream of TRPV1 activation, in patients with ongoing burning pain. In contrast, levels of Substance P, another neuropeptide often linked to pain signaling, did not differ between groups. This points to a specific involvement of the TRPV1-CGRP axis in this pain phenotype.

Clinically, these insights could pave the way for more targeted treatments. Capsaicin-based therapies, already approved for diabetic neuropathy, act directly on TRPV1. However, response rates have varied, possibly due to a lack of stratification based on sensory symptoms. The authors suggest that identifying patients based on pain phenotypes, such as those with predominant burning pain, could help tailor treatment more effectively.

The study acknowledges several limitations. Its cross-sectional design limits insight into the temporal dynamics of TRPV1 expression, and many patients reported overlapping symptoms, complicating efforts to isolate burning pain specifically. Nevertheless, the strong correlation between TRPV1 density and burning pain intensity, as measured by numerical rating scales, lends weight to the association.

Importantly, the study emphasizes that increased TRPV1 expression does not necessarily align with standard sensory testing results such as heat pain thresholds. This highlights the unique value of skin biopsy in identifying underlying pathophysiologic mechanisms that may be missed with traditional assessments.

As diabetic neuropathy continues to rise globally alongside type 2 diabetes, the need for precision in pain management is growing. This study supports the idea that TRPV1 is not only a marker of pain but also a potential key to unlocking more effective, phenotype-driven treatment strategies.

Source

Galosi, Eleonora; Falco, Pietro; Di Pietro, Giuseppe; Esposito, Nicoletta; De Stefano, Gianfranco; Evangelisti, Enrico; Leone, Caterina; Litewczuk, Daniel; Tramontana, Lorenzo; Di Stefano, Giulia; Truini, Andrea^*. Epidermal Transient Receptor Potential Vanilloid 1 innervation is increased in patients with painful diabetic polyneuropathy experiencing ongoing burning pain. PAIN 166(4):p 824-834, April 2025. | DOI: 10.1097/j.pain.0000000000003541