Background & Aims

Bortezomib-Induced Peripheral Neuropathy (BIPN) is frequently accompanied by reduced thermal sensation and neuropathic pain. TRPV1 is a pivotal thermal receptor implicated in burning pain. Our study aims to explore the potential relation between the expression of TRPV1 receptors on the skin and the development of pain symptoms in individuals with BIPN. The discovery of such a link might contribute to paving the way for more targeted and effective treatment strategies.

Methods

In this study, we employed immunofluorescence staining, combining PGP 9.5 and TRPV1 antibodies, on skin biopsy sections from 45 BIPN patients, including 27 individuals without and 18 with pain. A control group comprising 25 healthy volunteers was included. A total of 335 bioimages were collected and staining was quantified using custom designed image analysis (approximately 5 per person). Additionally, qPCR was utilized to measure TRPV1 mRNA expression in the skin. Quantitative sensory testing (QST) and pain questionnaires were employed to gather clinical data.

Results

TRPV1 Mean Fluorescence Intensity (TRPV1 MI) was decreased on nerve fibers in skin of BIPN patients compared to controls (p = 0.001). Further stratification based on pain demonstrated a more pronounced reduction in the subgroup experiencing pain (p = 0.027). Warm Detection Threshold (WDT), Cold Detection Threshold (CDT), thermal difference threshold (TDT), and heat pain detection threshold (HPDT) in patients with pain were notably increased compared to those without pain. TRPV1 MI (rs = -0.320, p = 0.032) and CDT (rs = -0.409, p = 0.005) exhibited a negative correlation with pain severity, while WDT (rs = 0.383, p = 0.009), TDT (rs = 0.561, p < 0.001), and HPDT (rs = 0.323, p = 0.031) were positively correlated. No significant differences in TRPV1 mRNA expression were observed between painful and painless patients' skin, indicating that cellular synthesis of TRPV1 was not altered, in contrast to TRPV1 localization on nerve fibers.

Conclusions

Diminished TRPV1 immunofluorescence on nerve fibers in BIPN patients with pain aligns with the insensitivity to thermal stimuli revealed by QST. This suggests that these findings are meaningful and may help to better understand the pathophysiology of pain in BIPN.

References

1. Julius, D. (2013). TRP channels and pain. Annu Rev Cell Dev Biol 29, 355-384. 10.1146/annurev-cellbio-101011-155833.
2.Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine, J.D., and Julius, D. (1997). The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816-824. 10.1038/39807.
3.Middleton, S.J., Barry, A.M., Comini, M., Li, Y., Ray, P.R., Shiers, S., Themistocleous, A.C., Uhelski, M.L., Yang, X., Dougherty, P.M., et al. (2021). Studying human nociceptors: from fundamentals to clinic. Brain 144, 1312-1335. 10.1093/brain/awab048.

Presenting Author

Yuying Jin

Poster Authors

Yuying Jin

OTHR

University of Wuerzburg

Lead Author

E-mail

Aishwarya Aravamudhan

Department of Animal Physiology, University of Leipzig

Lead Author

E-mail

Robert Kittel (Prof. Dr.)

Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Germany

Lead Author

E-mail

Claudia Sommer

Prof. Dr. MD

Institute for neurology, university hospital Würzburg, Germany

Lead Author

E-mail

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral