The long-range goal of this proposal is to develop an understanding of the etiology of chronic functional pain syndromes, such as fibromyalgia (FM) and irritable bowel syndrome (IBS). The constellation of symptoms in the FM and IBS suggest a failure to appropriately activate pain modulatory mechanisms, a failure to activate neuroendocrine stress mechanisms, and an alteration in the autonomic response. Our general hypothesis is that a neurobiological model exists in patients with FM and IBS, which includes as its primary components alterations in the following CNS responses to stressors: inadequate antinociceptive response, blunted hypothalamic-pituitary-adrenal (HPA) axis response and altered autonomic balance and responsiveness. By applying similar methodologies across two functional pain syndromes (FM, IBS, and IBS plus FM), we will elucidate if altered CNS circuits are shared by these functional disorders or are site-specific and may explain the differences in symptom expression in the somatic or visceral domains.
The first aim i s compare the visceral and somatic pain thresholds before and after a noxious conditioning stimulus in three female patient populations (IBS, FM and IBS plus FM) with female controls, which would allow us to determine if altered perceptual responses are due to hypersensitive afferent pathways, or to a failure to activate antinociceptive systems. To further characterize alterations in the activation of specific antinociceptive pathways in response to conditioning stimuli, we will assess the effect of pharmacological manipulations of the opioid system (fentanyl, naloxone), and the noradrenergic system (corticotropin-releasing hormone (CRH), dexamethasone) on pain thresholds. Finally, we will compare brain activation in regions known to play central roles in antinociception in the 4 study populations with H215O PET brain imaging during visceral and somatic stimuli before and after the conditioning stimulus. In the second aim, we will test the responsiveness of the HPA axis, which has been shown to be altered in patients with FM, in the 4 study populations and address the potential mechanisms to explain these HPA axis alterations. To characterize these alterations, we will obtain serial measurements of plasma cortisol and ACTH over a 24-hour period to assess baseline alterations in the diurnal pulsatile rhythm and synchrony of ACTH and cortisol. We will also assess HPA axis responsiveness to acute stress by comparing ACTH and cortisol levels before and after a visceral or somatic conditioning stimulus. Finally, in our third aim, we will compare autonomic responses to visceral and somatic stimuli during visceral and somatic conditioning paradigms. In order to determine if the response of central autonomic networks to visceral or somatic stimulation differ between the study groups, regional brain activation will be correlated to autonomic responses during the visceral and somatic stimuli in the PET studies using covariate analysis. The combination of experimental approaches should improve our understanding of the CNS mechanisms underlying functional pain syndromes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046122-03
Application #
6375225
Study Section
Special Emphasis Panel (ZAR1-BHD-B (J1))
Program Officer
Ader, Deborah N
Project Start
1999-09-13
Project End
2004-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
3
Fiscal Year
2001
Total Cost
$255,150
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Videlock, Elizabeth J; Shih, Wendy; Adeyemo, Mopelola et al. (2016) The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression. Psychoneuroendocrinology 69:67-76
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Chang, Lin (2011) The role of stress on physiologic responses and clinical symptoms in irritable bowel syndrome. Gastroenterology 140:761-5
Spiegel, Brennan M R; Farid, Mary; Esrailian, Eric et al. (2010) Is irritable bowel syndrome a diagnosis of exclusion?: a survey of primary care providers, gastroenterologists, and IBS experts. Am J Gastroenterol 105:848-58
Videlock, Elizabeth J; Adeyemo, Mopelola; Licudine, Arlene et al. (2009) Childhood trauma is associated with hypothalamic-pituitary-adrenal axis responsiveness in irritable bowel syndrome. Gastroenterology 137:1954-62
Chang, L; Sundaresh, S; Elliott, J et al. (2009) Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome. Neurogastroenterol Motil 21:149-59
Adeyemo, Mopelola A; Chang, Lin (2008) New treatments for irritable bowel syndrome in women. Womens Health (Lond Engl) 4:605-22;quiz 623
Spiegel, Brennan M R; Chey, William D; Chang, Lin (2008) Bacterial overgrowth and irritable bowel syndrome: unifying hypothesis or a spurious consequence of proton pump inhibitors? Am J Gastroenterol 103:2972-6

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