Role of the Nav 1.5 channel in peripheral sensory neurons in the development of nociceptive and neuropathic pain

• Grant number: 24/10827-4
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2025
• End date: April 30, 2028
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Thiago Mattar Cunha
• Grantee: Thiago Mattar Cunha
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Danilo Roman Campos

Abstract

Nociceptive/physiological pain is one of the main protective mechanisms that animals have developed to deal with the environment (external and internal), without which, the survival of the being is threatened. On the other hand, in certain situations, functional changes in the nociceptive system lead to the development of pain considered pathological, including neuropathic pain. Neuropathic pain is a disease of the somatosensory system that can result from several etiological factors, such as mechanical, biological, metabolic or chemical insults. Several factors are associated with the onset, maintenance and chronification of neuropathic pain, among them, voltage-gated sodium channels have been shown to play a significant role in this pathological context. These channels are involved in the transduction, transmission and propagation of nociceptive stimuli, and their importance is fundamental for pain. Preliminary data from our group have shed light on an unknown role of the Nav1.5 sodium channel in dorsal root ganglion neurons. Our unpublished results show that the gene encoding Nav1.5, Scn5a, is enriched in peripheral sensory neurons classified with Ad-LTMR fibers, which harbor the TrkB receptor, in both mice and humans. This subpopulation of peripheral sensory neurons has been identified as being extremely important for the manifestation of the symptom of allodynia in cases of neuropathic pain, while they have no role in nociceptive pain. Furthermore, when we reduced the expression of the Scn5a gene by interference RNA, we observed a reduction in mechanical allodynia in mice subjected to chemotherapy-induced neuropathic pain. Taken together, these results point to a possible role for Nav1.5 in neuropathic pain. As such, this project aims to further investigate the role of Nav1.5 expressed by TrkB+ sensory neurons in the processes of nociceptive and neuropathic pain. To achieve this goal, molecular, genetic, behavioral and electrophysiological approaches will be employed to dissect the role of Nav1.5 in the nociceptive system and its involvement in different models of neuropathic pain. Proof of this hypothesis would add an important and unprecedented concept to the field of chronic pain research, suggesting a new target for more effective therapies in relation to analgesic mechanisms. (AU)