Neuropathic pain is a chronic condition characterized by sensory, cognitive and affective symptoms. Most of the drugs used to treat this disorder demonstrate low efficacy and major side-effects. Understanding the epigenetic and transcriptional mechanisms that modulate the transmission and maintenance of peripheral nerve injury (PNI) symptoms will be a major step towards the development of novel treatment approaches. Our earlier findings identified a key role of the epigenetic modifier Histone deacetylase 5 (HDAC5) in the onset of action and efficacy of antidepressants in models of neuropathic pain. HDAC5 in the Nucleus Accumbens (NAc) binds to chromatin complexes to suppress the expression of several genes that affect synaptic function, including the transcription factor MEF2C. The parent R01 proposal investigates the mechanism by which HDAC5 and downstream targets modulate the actions of antidepressants in the NAc. This supplement project aims to elucidate cell type-specific epigenetic and transcriptomic mechanisms mediating the antiallodynic effects of monoamine-targeting antidepressants in models of neuropathic pain. Bioinformatic analysis of single nuclei RNASeq data will complement findings on HDAC5 and MEF2C actions and will also provide insight on transcriptomic events associated with antidepressant efficacy. We will validate key findings using fluorescent in situ hybridization, immunofluorescence, as well as western blot analysis. Pharmacological and genetic models will be use to test selected genes/intracellular pathways. Understanding the molecular mechanisms mediating the actions of monoamine-targeting antidepressants will help the development of novel and more efficacious medications for the treatment of neuropathic pain.

Public Health Relevance

This project examines cell type specific mechanisms that modulate of neuropathic pain states and the actions of antidepressants in the brain reward center. Findings from this work will provide important new information for safer, efficacious and better tolerated treatments for neuropathic pain conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS086444-07S1
Application #
10303381
Study Section
Program Officer
Mohapatra, Durga Prasanna
Project Start
2021-02-01
Project End
2022-07-31
Budget Start
2021-02-01
Budget End
2021-05-31
Support Year
7
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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