Pain can be a serious medical problem. While it is firmly established that hyperexcitability of dorsal root ganglion (DRG) sensory neurons often contributes to neuropathic and inflammatory pain, the cellular and molecular changes that underlie this hyperexcitability are not fully understood. This lack of knowledge has hindered the development of better therapeutics. Studies indicate that sodium channel properties are altered by inflammation and nerve injury. We have compelling evidence that increased resurgent current activity is involved in abnormal electrical excitability in sensory neurons, and in inherited and acquired pain syndromes. Although these currents are crucial determinants of spontaneous and high-frequency firing in neurons, our understanding of the molecular mechanisms that regulate them in sensory neurons is incomplete. We have developed in vivo and in vitro approaches for manipulating proteins involved in resurgent current generation that uniquely positions us to investigate the roles of these currents in sensory neuron function. In this project we propose to 1) Determine how Fibroblast Growth Factor Homologous Factors (FHFs) regulate Nav?4?s ability to generate resurgent currents in DRG neurons. 2) Determine crucial molecular determinants of resurgent current generation. 3) Identify the roles of TTX-R and TTX-S resurgent currents in selected pain conditions, including peripheral inflammation, oxaliplatin-induced neuropathy, sickle cell disease and inherited small fiber neuropathy. 4) Determine how cannabinoids target resurgent currents in sensory neurons. This research will provide fundamental insight into how resurgent sodium currents are regulated and how they can be manipulated, increasing our knowledge of cellular and molecular mechanisms of pain and facilitating the discovery of new therapeutics for pain and other disorders of cellular excitability.

Public Health Relevance

Pain is a serious medical problem, but the available treatments are often only partially effective and are limited by their side effects. Incomplete understanding of the mechanisms that contribute to chronic pain has hindered the development of better therapeutics. We have identified a novel ionic current in pain sensing neurons that likely contributes to chronic pain and therefore could be a good target for treating pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053422-13
Application #
9750827
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Oshinsky, Michael L
Project Start
2006-01-19
Project End
2020-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
13
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pharmacology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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