Diminished transient receptor vanilloid 1 on skin nerve fibers in painful bortezomib-induced peripheral neuropathy

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ABSTRACT: Bortezomib-induced peripheral neuropathy (BIPN) is frequently accompanied by reduced thermal sensation and neuropathic pain. We explored the relation between transient receptor vanilloid 1 (TRPV1) receptors on skin nerves and BIPN pain. We combined PGP9.5 and TRPV1 immunofluorescence labelling on skin biopsy sections from 67 individuals, 27 patients with BIPN without pain, 18 patients with BIPN with pain, and 22 healthy volunteers. A total of 332 bioimages were collected and quantified using objective image analysis. qPCR was used to measure TRPV1 mRNA in the skin. Quantitative sensory testing and pain questionnaires were used to gather clinical data. Transient receptor vanilloid 1 immunoreactivity appeared as distinct puncta along the nerve fibers. Its normalized mean fluorescence intensity (TRPV1/PGP9.5 MFI) ( P < 0.05) and TRPV1 puncta area ( P < 0.001) were decreased in small nerve fibers of patients with BIPN, concomitantly with reduced thermal sensitivity. Further stratification based on pain symptoms demonstrated a greater reduction in TRPV1/PGP9.5 MFI and severe impairment in thermal difference detection ability (TSL) and heat pain thresholds (HPT) in painful BIPN. Pain levels were negatively correlated with TRPV1/PGP9.5 MFI in the epidermis and subepidermis ( P < 0.001 r = -0.44; P < 0.001, r = -0.42), and with z-scores of TSL and HPT ( P < 0.05; P < 0.05). Transient receptor vanilloid 1 mRNA levels in skin were not different between groups, indicating that cellular synthesis of TRPV1 was not altered. Diminished TRPV1 immunoreactivity on nerves of patients with BIPN with pain aligns with their insensitivity to thermal stimuli which may help to better understand the pathophysiology of pain in patients with BIPN.

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