The transition from acute to chronic neuropathic pain following nerve injury, in many respects, results from a maladaptive plasticity of the nervous system, i.e. it is a disease of the nervous system. The plasticity is manifest at molecular, structural, biochemical and physiological levels, all leading to a condition in which there is ongoing, intense spontaneous pain, pain in response to normally innocuous stimuli (allodynia) and exaggerated pain in response to normally painful stimuli (hyperalgesia). The initiation and maintenance of neuropathic pain involves remodeling of injured nerve circuits, changes in synaptic strength as the pain message is processed through the spinal cord and brain as and perturbations in signaling processes, at all levels of the "pain" pathway. Many of these changes, however, are the product and/or the cause of long lasting alterations in gene expression. As the most stable modulation of gene expression programs is under epigenetic regulatory control, here we will perform studies to test the hypothesis that nerve injury induces significant alterations to the neuronal epigenome, and most importantly that some of these changes contribute to the generation and persistence of the neuropathic pain condition. In other words, we will dissect the epigenetic landscape of chronic neuropathic pain. Our initial studies will focus on changes that occur in the spinal cord following nerve injury, in standard rodent models of neuropathic pain. Our objective is to obtain a better understanding of the molecular underpinnings of this maladaptive process, which is a critical first step to identifying new targets for therapeutic intervention.

Public Health Relevance

Nerve injury-induced chronic neuropathic pain is a maladaptive neuronal process, of unknown etiology, that affects the quality of life of millions of Americans. Here, we propose experiments that will reveal the epigenetic and genetic contributors to this condition, with the objective of obtaining a better understanding of the molecular underpinnings of neuropathic pain, but also of identifying novel targets for effective therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE022001-02
Application #
8306618
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (51))
Program Officer
Kusiak, John W
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$386,250
Indirect Cost
$136,250
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143