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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Oshinsky, Michael L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
Zip Code
Shugg, Tyler; Johnson, Derrick E; Shao, Minghai et al. (2018) Calcium/calmodulin-dependent protein kinase II regulation of IKs during sustained ?-adrenergic receptor stimulation. Heart Rhythm 15:895-904
Barbosa, Cindy; Xiao, Yucheng; Johnson, Andrew J et al. (2017) FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons. Pflugers Arch 469:195-212
Ohlemacher, Sarah K; Sridhar, Akshayalakshmi; Xiao, Yucheng et al. (2016) Stepwise Differentiation of Retinal Ganglion Cells from Human Pluripotent Stem Cells Enables Analysis of Glaucomatous Neurodegeneration. Stem Cells 34:1553-62
Xie, Wenrui; Tan, Zhi-Yong; Barbosa, Cindy et al. (2016) Upregulation of the sodium channel NaV?4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation. Pain 157:879-91
Pei, Zifan; Xiao, Yucheng; Meng, Jingwei et al. (2016) Cardiac sodium channel palmitoylation regulates channel availability and myocyte excitability with implications for arrhythmia generation. Nat Commun 7:12035
Patel, Reesha R; Barbosa, Cindy; Brustovetsky, Tatiana et al. (2016) Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol. Brain 139:2164-81
Torregrosa, Robert; Yang, Xiao-Fang; Dustrude, Erik T et al. (2015) Chimeric derivatives of functionalized amino acids and ?-aminoamides: compounds with anticonvulsant activity in seizure models and inhibitory actions on central, peripheral, and cardiac isoforms of voltage-gated sodium channels. Bioorg Med Chem 23:3655-66
Barbosa, Cindy; Tan, Zhi-Yong; Wang, Ruizhong et al. (2015) Nav?4 regulates fast resurgent sodium currents and excitability in sensory neurons. Mol Pain 11:60
Patel, Reesha R; Barbosa, Cindy; Xiao, Yucheng et al. (2015) Human Nav1.6 Channels Generate Larger Resurgent Currents than Human Nav1.1 Channels, but the Nav?4 Peptide Does Not Protect Either Isoform from Use-Dependent Reduction. PLoS One 10:e0133485
Chen, Xingjuan; Sun, Weiyang; Gianaris, Nicholas G et al. (2014) Furanocoumarins are a novel class of modulators for the transient receptor potential vanilloid type 1 (TRPV1) channel. J Biol Chem 289:9600-10

Showing the most recent 10 out of 44 publications