Although we are at the end of the Congressionally-declared Decade for Pain Control and Research, chronic pain continues to be a leading public health epidemic, affecting more than 50 million Americans and costing more than $165 billion per year in treatment expenses and lost work productivity. Of particular note are those patients with chronic diseases, such as cancer and HIV, who suffer from treatment-related pain that cannot be controlled with conventional analgesics. Treatment-related pain affects approximately 50% of these patients, depending on drug and dosing regimen, which translates into nearly 700,000 Americans per year. The predominant symptom is excruciating unremitting pain that is resistant to traditional pharmacological treatments. As therapeutics become increasingly aggressive and diseases become chronic, this becomes a risk/benefit issue;patients must choose between increased life expectancies and constant suffering with decreased quality of life. This decision is untenable, and thus, the crucial question that must be answered is how to prevent or reverse persistent disease treatment-related pain. Recent mechanistic studies have found that the development and persistence of neuropathic pain stems in part from central sensitization in the spinal dorsal horn. Much like memory formation in the hippocampus, central sensitization in the spinal cord produces pain hypersensitivity that is uncoupled from noxious input. More simply put, innocuous inputs produce long lasting pain hypersensitivity. Recently, we made the preliminary discovery that antiretroviral treatment produces up-regulation of Brain-derived Neurotrophic Factor (BDNF) in the mouse spinal dorsal horn, causing central sensitization (hyperexcitability of spinal dorsal horn neurons) and the development and persistence of nocifensive (pain) behavior. Reducing levels of BDNF expression in vivo reversed this phenotype. These data implicating BDNF in treatment-related pain suggest that BDNF may represent a new target for drug development. However, further studies to determine precisely how chemotherapeutic drugs alter BDNF expression and that of the BDNF receptor, tyrosine kinase receptor B (trkB) are crucial first steps. One likely possibility is via epigenetic regulation of BDNF and trkB gene expression. In support of this idea, we have shown that alterations in DNA methylation and histone modifications in promoter regions produce changes in BDNF gene expression that regulate the capacity for long-term memory formation. Thus, we hypothesize that complex epigenetic regulation of BDNF and trkB may produce gene dysregulation that is mechanistically linked to long-term chemotherapy-induced neuropathic pain. In addition, we posit that other genes, not previously linked with nociception, may undergo epigenetic regulation and we will examine this question using chromatin immunoprecipitation (ChIP) followed by high-throughput next generation sequencing (ChIP-seq). Results from these studies will have broad impact beyond treatment-related pain to improve our understanding of chronic pain persistence and the role for epigenetic modifications.

Public Health Relevance

While potentially curative, the drugs used to treat patients with cancer and HIV/AIDS can produce a long- lasting pain. Occurring in some, but not all patients, this treatment-related pain complication is difficult to manage with conventional pain medications and so patients suffer with unrelieved pain. The results from the proposed studies may help us to understand treatment-related pain in more detail, and may provide new molecular targets for analgesic therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
5R01NR012686-02
Application #
8151028
Study Section
Special Emphasis Panel (ZNR1-REV-T (02))
Program Officer
Tully, Lois
Project Start
2010-09-28
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$672,810
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Nursing
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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