Background & Aims

It has been reported that patients with neuropathy can present with or without neuropathic pain (NP). The mechanisms behind this are still not well understood. Studies focus on differentiating these groups for more targeted treatments. Preclinical research has studied cyclin-dependent kinase 5 (CDK5) and its role in pain signaling. The binding of Cdk5/p35 has been shown to be important in NP and phosphorylates some receptors involved in pain. However, this has not been studied in humans. We aim to determine if CDK5 activity is enhanced in patients with painful neuropathy. The general aim of the study is to investigate the role of Cdk5/p35 in painful and non-painful small fiber neuropathy (SFN). The specific aims are: to identify patients with Painful and non-painful SFN; to assess CDK5 and p35 messenger levels and expression in both groups; to evaluate the levels and expression of TRPV1, P2XRs, and Kvs in both groups; and to correlate sensory profiles with pathway activation in both.

Methods

We are recruiting adult patients with suspicion of SFN, both with and without pain. Patients attend a single appointment during which they provide demographic characteristics, fill screening questionnaires, and have their somatosensory profile assessed through Quantitative Sensory Test (QST) at the foot and at the thigh. In addition, two skin biopsies are taken from the lower leg, one is used for immunostaining with PGP9.5 and assessing the IENFD. Patients with a confirmed SFN are divided into two groups (painful and non-painful). The second skin biopsy will be used to evaluate messenger levels and protein immunolocalization of CDK5, p35, and potential Cdk5 targets (TRPV1, P2X2/3R and Kvs Kv1.2, Kv1.6 and Kv2.1). The sensory profile will be correlated with messenger and protein levels of CDK5/p35 or CDK5 targets in patients with painful and non-painful SFN. Patients that did not reach diagnosis of small fibre neuropathy will be classified as control volunteers with or without pain.

Results

We have recruited 100 subjects so far: 46 with painful SFN, 18 with non-painful SFN, 24 healthy controls, and 12 subjects with pain but without neuropathy. The participants were characterized through clinical signs, quantitative sensory testing, and skin biopsies. In the quantitative sensory tests, both the painful and non-painful SFN groups exhibited hyposensitivity to thermal stimuli and showed a higher prevalence of paradoxical heat sensations compared to the non-neuropathy controls. In skin biopsies, patients with SFN, regardless of the presence of pain, exhibited significantly lower intraepidermal nerve fiber density compared to healthy controls and patients with pain but no neuropathy. Concomitantly, we performed preliminary qPCR trials in the skin. We observed an increase in CDK5 mRNA levels SFN groups. Furthermore, we noted a decrease in CDK5R1 (p35) mRNA levels in SFN groups compared to non-neuropathy controls. But we observed no significant difference between SFN groups.

Conclusions

There is an upregulation of CDK5 mRNA in the skin of patients with painful small fiber neuropathy (SFN), and a downregulation of CDK5R1 mRNA in the skin of all SFN patients compared to controls. This needs to be validated once recruitment is completed. Our future data could help understand the differences between painful and non-painful SFN and may provide a target for the development of biomarkers or personalized treatment approaches for SFN.

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Presenting Author

Gustavo Torres Riveros

Poster Authors

Gustavo Torres

PT

Pontificia Universidad Católica de Chile

Lead Author

Macarena Tejos

Pontificia Universidad Catolica de Chile

Lead Author

Dixon Cid

Lead Author

Mauricio Reyna

Lead Author

Elias Utreras

Lead Author

Claudio Caddou

Lead Author

Margarita Calvo

Pontificia Universidad Católica de Chile

Lead Author

Topics

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