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"Endothelin Type A Receptors Mediate Pain in Sickle Cell Disease Through NF-B-Induced Nav1.8 Upregulation in Primary Sensory Neurons"

Brianna Lutz
Cell Biology, Neuroscience and Physiology Program
B.S. 2012, Lycoming College, Williamsport, PA

Thesis Advisor: Yuan-Xiang Tao, MD, PhD
Professor & Vice Chair of Research
Department of Anesthesiology
Rutgers New Jersey Medical School

Monday, October 9, 2017
1:30 P.M., MSB Room B610


Sickle Cell Disease (SCD) is associated with acute painful episodes and persistent intractable pain that are not effectively and consistently alleviated by opioids or hydroxyurea. Identifying the molecular mechanisms of SCD-associated pain can reveal novel targets for therapeutic intervention. Endothelin-1, a known pain inducer, is elevated in the blood plasma of both SCD patients and SCD mouse models. In addition, inhibition of the endothelin-type A (ETA) receptor alleviated pain hypersensitivity in mouse models of chronic pain. This study analyzed the pain phenotype of two mouse models of SCD and identified a novel mechanism of SCD-associated pain mediated by ETA receptors. Berkeley and Townes SCD mice displayed evoked pain hypersensitivity, and Townes SCD mice exhibit spontaneous pain. Electrophysiology and biochemical analysis of the dorsal root ganglia (DRG) of SCD mice revealed an increase in neuronal excitability, ET-1 and ETA receptor expression, and Nav1.8 current and expression. Pharmacologic inhibition or sensory neuron-specific knockdown of ETA receptors alleviated basal and post-hypoxia evoked pain hypersensitivities in SCD mice. Mechanistically, ETA receptors mediate SCD-associated pain through the activation of NF-B and subsequent Nav1.8 upregulation in the DRG neurons. These findings reveal a new ETA receptor-dependent NF-B and Nav1.8 pathway in the DRG that underlies a mechanism of SCD-associated pain and may provide a novel strategy for the management of SCD pain.

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