Vorschau

PDF, Englisch (PhD thesis Rahul Dhandapani) - Hauptdokument Download (5MB) | Nutzungsbedingungen

Abstract

Mechanical allodynia is a type of neuropathic pain in which innocuous touch evokes severe pain. Despite several years of research, the primary sensory neurons that mediate allodynia still remain unidentified. In this study, we demonstrate that a population of low threshold mechanoreceptors expressing TrkB mediates the input that produces pain from light touch after nerve injury. Using an inducible Cre line driven from the TrkB gene locus, we show that TrkB is expressed in Dhairs and RA Ab-mechanoreceptors. Ablation of TrkB positive neurons leads to reduction in sensitivity to the gentle touch under naïve conditions, and failure to develop mechanical allodynia in a nerve injury model of neuropathic pain. Also, selective optogenetic activation of these neurons evokes marked nocifensive behavior after nerve injury. Furthermore, we develop a phototherapeutic strategy based on the ligand for TrkB to perform ligand-mediated photoablation of TrkB positive afferents. Using this approach we show that selective photo-ablation of TrkB afferents in the skin results in a pronounced rescue of mechanical allodynia in multiple models of neuropathic pain. We thus identify the peripheral neurons which transmit pain from light touch and establish a novel therapeutic strategy for its treatment.