The overall goal of this project is to determine the contribution of sensory neuron mitochondrial dysfunction and TRP channel sensitization to pain in sickle cell disease (SCD), including the development of chronic pain. SCD is accompanied by crippling pain during acute sickling episodes that increases in severity and frequency with age. By adulthood, approximately 50% of SCD patients also suffer from chronic pain. SCD involves repeated ischemia-reperfusion injury and increased neutrophil numbers/activity, which results in elevated reactive oxygen species (ROS) generation and oxidative stress. This can lead to mitochondrial dysfunction and sensitization of Transient Receptor Potential (TRP) ion channels. We show that mice with severe SCD exhibit evidence for ongoing pain and pronounced pain-like behavior in response to cold, mechanical and heat stimuli. Our preliminary data also indicate that sensory neurons from sickle mice have severely dysfunctional mitochondria. We hypothesize that ROS and oxidative stress induce mitochondrial dysfunction and TRP channel sensitization in sickle sensory neurons, leading to the chronic pain and thermal hypersensitivity that is characteristic of this devastating disease.
Aim 1 will determine the time course of neuronal mitochondrial dysfunction and pain sensitivity in sickle mice from age 2 to 12 weeks.
Aim 2 will determine whether sensitized TRPA1 or TRPM8 channels underlie the cold hypersensitivity and primary afferent sensitization in sickle mice.
Aim 3 will determine whether treatment with mitochondrial-targeted antioxidants reverses the pain behavior and primary afferent sensitization in sickle mice. These interrelated Aims provide a multifaceted approach that will define the mechanisms by which mitochondrial dysfunction and TRP channel sensitization lead to the devastating pain observed in SCD. Furthermore, this study targets specific cold-sensitive ion channels (TRPA1 and TRPM8) on sensory neurons because cold pain and cold hypersensitivity are a major complaint of patients with SCD. Data from this study will improve our understanding of the complex SCD pain syndromes and should aid in identifying novel therapeutic targets

Public Health Relevance

Sickle cell disease is an inherited disorder of the red blood cell causing a shape change and clogging blood vessels, resulting in severe pain and suffering. The pain and disability are even more severe in adults than in children. In this grant, we intend to study the precise nerve cells and pathways that sense and influence the pain so that we can develop new methods to treat sickle cell disease more safely and effectively.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01NS070711-05
Application #
8708438
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Oshinsky, Michael L
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Garrison, Sheldon R; Stucky, Cheryl L (2014) Contribution of transient receptor potential ankyrin 1 to chronic pain in aged mice with complete Freund's adjuvant-induced arthritis. Arthritis Rheumatol 66:2380-90
Larson, Michael Craig; Hillery, Cheryl A; Hogg, Neil (2014) Circulating membrane-derived microvesicles in redox biology. Free Radic Biol Med 73:214-28
Garrison, Sheldon R; Weyer, Andy D; Barabas, Marie E et al. (2014) A gain-of-function voltage-gated sodium channel 1.8 mutation drives intense hyperexcitability of A- and C-fiber neurons. Pain 155:896-905
Dranka, Brian P; Gifford, Alison; McAllister, Donna et al. (2014) A novel mitochondrially-targeted apocynin derivative prevents hyposmia and loss of motor function in the leucine-rich repeat kinase 2 (LRRK2(R1441G)) transgenic mouse model of Parkinson's disease. Neurosci Lett 583:159-64
Zappia, Katherine J; Garrison, Sheldon R; Hillery, Cheryl A et al. (2014) Cold hypersensitivity increases with age in mice with sickle cell disease. Pain 155:2476-85
Hanson, Madelyn S; Xu, Hao; Flewelen, Timothy C et al. (2013) A novel hemoglobin-binding peptide reduces cell-free hemoglobin in murine hemolytic anemia. Am J Physiol Heart Circ Physiol 304:H328-36
Tsunozaki, Makoto; Lennertz, Richard C; Vilceanu, Daniel et al. (2013) A 'toothache tree' alkylamide inhibits Aýý mechanonociceptors to alleviate mechanical pain. J Physiol 591:3325-40
Gemes, Geza; Koopmeiners, Andrew; Rigaud, Marcel et al. (2013) Failure of action potential propagation in sensory neurons: mechanisms and loss of afferent filtering in C-type units after painful nerve injury. J Physiol 591:1111-31
Brandow, Amanda M; Stucky, Cheryl L; Hillery, Cheryl A et al. (2013) Patients with sickle cell disease have increased sensitivity to cold and heat. Am J Hematol 88:37-43
Garrison, Sheldon R; Dietrich, Alexander; Stucky, Cheryl L (2012) TRPC1 contributes to light-touch sensation and mechanical responses in low-threshold cutaneous sensory neurons. J Neurophysiol 107:913-22

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