Epidermal Transient Receptor Potential Vanilloid 1 innervation is increased in patients with painful diabetic polyneuropathy experiencing ongoing burning pain

Abstract Preclinical studies suggested that Transient Receptor Potential Vanilloid 1 (TRPV1) channels contribute to neuropathic pain in animal models of diabetic polyneuropathy. Patients with painful diabetic polyneuropathy commonly experience ongoing burning pain. This study aimed at evaluating the association between this specific type of pain and TRPV1 intraepidermal nerve fibers in patients with painful diabetic polyneuropathy. We consecutively enrolled 70 patients with diabetic polyneuropathy. Each patient completed the Neuropathic Pain Symptom Inventory (NPSI) to identify the various types of neuropathic pain. All patients underwent a distal leg skin biopsy, with immunostaining of skin nerve fibers using antibodies for the pan-axonal marker Protein Gene Product 9.5 (PGP9.5), TRPV1, Calcitonin Gene-Related Peptide (CGRP), and Substance P. We found that 57% of patients (n = 40) had neuropathic pain symptoms, with ongoing burning pain being the most frequently reported type of pain at the NPSI (70% of patients with pain, n = 28). Patients with ongoing burning pain had higher TRPV1 intraepidermal nerve fiber density and TRPV1/PGP9.5 ratio compared with those with painless polyneuropathy ( P = 0.014, P = 0.013) and painful polyneuropathy with other types of pain ( P < 0.0001, P = 0.024); they also had increased CGRP dermal nerve fiber density compared with patients with painless polyneuropathy ( P = 0.005). Our study showed that ongoing burning pain is associated with an increased expression of intraepidermal TRPV1 fibers, as well as an increased dermal representation of CGRP fibers. These findings suggest that TRPV1 contributes to ongoing burning pain, possibly in conjunction with elevated CGRP expression, highlighting its significance as a therapeutic target for patients with painful diabetic polyneuropathy.