The objective of our study is to elucidate the mechanisms underlying the sexually dimorphic effects of early life stress (ELS) on pain perception in female veterans. Our overarching hypothesis is that exposure to adversity in early life predisposes female veterans to heightened visceral pain via a central mechanism involving abnormalities in brain-gut communication. RESEARCH PLAN:
Under Specific Aim 1, we will test the hypothesis that stress in early life serves as a risk factor for heightened pain in adulthood produced by chronic stress. Having identified in preliminary experiments increases in stress-responsive genes within the central nucleus of the amygdala (CeA) of female rats exposed to ELS, in Specific Aim 2 we will test the hypothesis that heightened pain perception in adulthood following ELS is mediated by central increases in stress-responsive genes.
Specific Aim 3 will explore the hypothesis that centrally driven epigenetic changes make an individual more susceptible to chronic stress and contribute to the sexually dimorphic effects of ELS on pain perception in adult female rats. METHODOLOGY: We will employ validated rats models that recapitulate visceral pain in patients. Specifically, we will measure colonic sensitivity by quantifying the number of abdominal cramps in response to colonic distension. Stress in early life will be induced by odor shock conditioning in neonatal rat pups. Stress in adulthood will result from repeated exposure for 1 hour each day to a water avoidance stressor (WAS). We will investigate whether ELS serves as a predisposing risk factor for heightened visceral pain in response to chronic WAS in adulthood. We also will investigate whether knockdown of amygdaloid gene expression using specific antisense oligodeoxynucleotides (ODNs) inhibits the development of pain following ELS. Finally we will use an array of epigenetic approaches targeting histone acetyltransferases within the CeA to gain further mechanistic insight into stress-induced visceral pain. ANTICIPATED RESULTS:
For Specific Aim 1 we expect to show that rats experiencing adult stress will have visceral hypersensitivity compared to controls. However, we anticipate that that there will be a greater visceral sensitivity to the adult stress following ELS. We also expect an exaggerated activation of the HPA axis indicated by an elevated systemic CORT and ACTH, as well as increased fecal pellet output (FPO) in response to WAS in all experimental groups, however the magnitude of the change will be greater in response to ELS.
For Specific Aim 2, we anticipate that imbalances of stress responsive genes contribute to abnormal visceral pain perception in adulthood following ELS. In experiments proposed under specific aim 3 we expect to show that heightened visceral pain following ELS may be modulated through epigenetically mediated mechanisms within the CeA.

Public Health Relevance

TO VETERANS HEALTH: The VA provides specialized health care for female veterans, however limited research has focused on illnesses experienced by female Veterans. Of importance to this proposal, female veterans with anxiety-related disorders have higher rates of childhood abuse. Our findings may identify novel approaches to improve the treatment of pain in female Veterans.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001195-06
Application #
9210532
Study Section
Neurobiology B (NURB)
Project Start
2011-04-01
Project End
2019-09-30
Budget Start
2016-10-01
Budget End
2017-09-30
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Oklahoma City VA Medical Center
Department
Type
Independent Hospitals
DUNS #
020719316
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Latorre, R; Sternini, C; De Giorgio, R et al. (2016) Enteroendocrine cells: a review of their role in brain-gut communication. Neurogastroenterol Motil 28:620-30
Prusator, Dawn K; Greenwood-Van Meerveld, Beverley (2016) Sex-related differences in pain behaviors following three early life stress paradigms. Biol Sex Differ 7:29
Mohammadi, Ehsan; Prusator, Dawn K; Healing, Eleanor et al. (2016) Sexually dimorphic effects of early life stress in rat pups on urinary bladder detrusor muscle contractility in adulthood. Biol Sex Differ 7:8
Prusator, D K; Andrews, A; Greenwood-Van Meerveld, B (2016) Neurobiology of early life stress and visceral pain: translational relevance from animal models to patient care. Neurogastroenterol Motil 28:1290-305
Prusator, D K; Greenwood-Van Meerveld, B (2015) Gender specific effects of neonatal limited nesting on viscerosomatic sensitivity and anxiety-like behavior in adult rats. Neurogastroenterol Motil 27:72-81
Chaloner, Aaron; Greenwood-Van Meerveld, Beverley (2013) Early life adversity as a risk factor for visceral pain in later life: importance of sex differences. Front Neurosci 7:13
Chaloner, Aaron; Greenwood-Van Meerveld, Beverley (2013) Sexually dimorphic effects of unpredictable early life adversity on visceral pain behavior in a rodent model. J Pain 14:270-80
Myers, Brent; Schulkin, Jay; Greenwood-Van Meerveld, Beverley (2011) Sex steroids localized to the amygdala increase pain responses to visceral stimulation in rats. J Pain 12:486-94
Gustafsson, Jenny K; Greenwood-Van Meerveld, Beverley (2011) Amygdala activation by corticosterone alters visceral and somatic pain in cycling female rats. Am J Physiol Gastrointest Liver Physiol 300:G1080-5