Pain is a serious medical problem. While it is well known that hyperexcitability of dorsal root ganglion (DRG) sensory neurons can contribute 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. Changes in sodium currents can substantially alter the excitability of DRG neurons. We have found that mutations that cause paroxysmal extreme pain disorder (PEPD) can significantly increase resurgent sodium currents produced by Nav1.7 in DRG neurons. Furthermore, we have exciting new data indicating that a spinal cord injury that causes increased pain can significantly increase resurgent currents in DRG neurons. We propose that resurgent sodium currents contribute to spontaneous firing, hyperexcitability and the initiation of pain sensations in DRG sensory neurons. Unfortunately, our understanding of the molecular mechanisms that underlie resurgent currents, especially in DRG neurons, is poor. We have developed a neuronal expression system for recombinant voltage-gated sodium channels that uniquely positions us to investigate these currents. In this project we will: 1) Establish the molecular determinants of resurgent currents in DRG neurons. 2) Determine how resurgent currents are regulated by phosphorylation, inflammatory mediators, reactive oxygen species, acidity, and other modulators that impede fast-inactivation of sodium channels and contribute to enhanced pain sensations. 3) Determine if resurgent currents are sensitive to modulation by local anesthetics, anti-convulsants and other agents that target voltage-gated sodium channels. 4) Investigate the consequences of resurgent currents on sensory neuronal excitability. Identifying the molecular mechanisms underlying resurgent current generation will enhance our ability to identify the roles of these currents in pain and other disorders of excitability, and to develop therapeutic strategies specifically targeting resurgent currents.

Public Health Relevance

Pain is a serious medical problem. The currently 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 alteration in pain sensing neurons that likely contributes to chronic pain. Identifying the molecular mechanisms underlying this abnormal activity will enhance our ability develop enhanced strategies for treating chronic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS053422-07S1
Application #
8504397
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (03))
Program Officer
Whittemore, Vicky R
Project Start
2006-01-19
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$57,091
Indirect Cost
$17,312
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
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
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
Xie, Wenrui; Tan, Zhi-Yong; Barbosa, Cindy et al. (2016) Upregulation of the sodium channel NaVβ4 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
Barbosa, Cindy; Tan, Zhi-Yong; Wang, Ruizhong et al. (2015) Navβ4 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 Navβ4 Peptide Does Not Protect Either Isoform from Use-Dependent Reduction. PLoS One 10:e0133485
Torregrosa, Robert; Yang, Xiao-Fang; Dustrude, Erik T et al. (2015) Chimeric derivatives of functionalized amino acids and α-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
Lee, Hyosung; Park, Ki Duk; Torregrosa, Robert et al. (2014) Substituted N-(biphenyl-4'-yl)methyl (R)-2-acetamido-3-methoxypropionamides: potent anticonvulsants that affect frequency (use) dependence and slow inactivation of sodium channels. J Med Chem 57:6165-82
Tan, Zhi-Yong; Priest, Birgit T; Krajewski, Jeffrey L et al. (2014) Protein kinase C enhances human sodium channel hNav1.7 resurgent currents via a serine residue in the domain III-IV linker. FEBS Lett 588:3964-9
Tan, Zhi-Yong; Piekarz, Andrew D; Priest, Birgit T et al. (2014) Tetrodotoxin-resistant sodium channels in sensory neurons generate slow resurgent currents that are enhanced by inflammatory mediators. J Neurosci 34:7190-7
Xiao, Yucheng; Blumenthal, Kenneth; Cummins, Theodore R (2014) Gating-pore currents demonstrate selective and specific modulation of individual sodium channel voltage-sensors by biological toxins. Mol Pharmacol 86:159-67

Showing the most recent 10 out of 41 publications