Role of sodium channel Nav1.5 in TrKB positive sensory fibers in the development of paclitaxel-induced neuropathic pain

• Grant number: 24/04992-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2024
• End date: November 30, 2027
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Thiago Mattar Cunha
• Grantee: Francisco Isaac Fernandes Gomes Aragão
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

neuropathic pain is a disease of the somatosensory system that can result from different etiological factors such as mechanical, biological, metabolic, or chemical insults. Chemotherapeutic agents used to treat cancer can cause neuropathic pain (CINP) due to their neurotoxicity to primary sensory neurons, causing aberrant functioning of these cells and leading to long-lasting pain in cancer patients. This side-effect is among the leading causes of chemotherapy discontinuation, which is directly associated with cancer recurrence. Several factors are associated with the onset, maintenance, and chronification of CIPN, among them, voltage-gated sodium channels (VGSC) have demonstrated to play a significant role in this pathological context. VGSC have long been implicated in nociceptive input transduction and transmission/propagation, and their importance is paramount to pain. Preliminary data from our group has shed light on an unknown role for VGSC Nav1.5 in dorsal root ganglion (DRG) neurons. Our findings show that the gene encoding Nav1.5, Scn5a, is enriched in TrkB-positive neurons after paclitaxel-induced neuropathic pain by reanalyzes of single-cell RNA sequencing of DRG sensory neurons. Also, our bioinformatic approach revealed that Scn5a gene expression was the VGSC gene signature of TrkB neurons in the mouse and human DRG sensory neurons, a finding corroborated with RNA scope analysis of Snc5a expression by TrkB neurons. Furthermore, by decreasing Scn5a gene expression by siRNA, we attenuated the nociceptive behavior of wildtype mice subjected to paclitaxel-induced neuropathic pain. Altogether, these findings point toward a possible role of Nav1.5 in the paclitaxel-induced neuropathic pain. As such, this project aims to investigate the role of Nav1.5 in TrkB neurons upon paclitaxel-induced neuropathic pain. To achieve this purpose, molecular, genetic, behavioral, and electrophysiological approaches will be employed to dissect the role of Nav1.5 in the nociceptive system and its involvement in neuropathic pain after paclitaxel chemotherapy. Proving this hypothesis would add an unprecedented and important concept to the chronic pain research field, suggesting a new target for more efficacious therapies towards analgesic mechanisms.