Visceral pain is currently the leading cause for patient visits in the U.S and is the main debilitating aspect in irritable bowel syndrome (IBS). The incidence of IBS is higher among individuals who experienced adverse events during childhood, including verbal, physical and sexual abuse, as well as disease of later affected organs. The focus of the parent K01 proposal was a novel mouse model of neonatal colon irritation (NCI) that reproduced the principal characteristic of IBS - colon hypersensitivity in the absence of histopathology. The main hypothesis was that early insult in the viscerosensory system produces a long-lasting alteration in nociceptive processing at the level of the colon, peripheral nerve and DRG. The current proposal aims to broaden the focus of the original K01 award, by adding a model of neonatal stress (neonatal maternal separation [NMS]) to the ongoing studies of NCI in an attempt to gain a more complete understanding of the vulnerabilities of the developing viscerosensory system and the long-lasting deleterious effects that can result from perturbations during the neonatal critical period. The experiments in this application are outlined in two specific aims and are designed to functionally test the hypothesis that NMS produces lifelong visceral hypersensitivity in mice through heightened excitability of peripheral sensory neurons due to changes in expression of specific membrane receptors, which exacerbate the response to experimental colitis. SA1: To test the hypothesis that NMS in mice produces long-lasting colon hypersensitivity and increased excitability/receptor changes in peripheral nerves innervating the distal colon. To test this hypothesis, a) the visceromotor response (VMR) to colorectal distension will be evaluated in adult NMS mice and b) single cell RT-PCR and calcium imaging will be performed on colon DRG neurons to determine changes in expression, function and interactions between TRPV1 and TRPA1, two channels proposed to regulate visceral sensitivity. SA2: To test the hypothesis that NMS enhances susceptibility to experimental colitis and exacerbates inflammation-induced changes in the distal colon and associated peripheral sensory neurons. To test this hypothesis, trinitrobenzene sulfonic acid (TNBS) will be administered to induce colitis and a) the extent of inflammation will be determined by assessing increases in myeloperoxidase (MPO) activity and growth factor production, and b) VMR, single cell RT-PCR and calcium imaging will be repeated to determine how colitis affects the already altered nociceptive processing in the NMS mice. The addition of the NMS model to ongoing studies of NCI allows for comparisons to be made between two different models of neonatal insult with the same behavioral outcome, heightened visceral sensitivity. Discoveries made using these models will allow for the identification of common and/or divergent pathways that underlie visceral hypersensitivity, which could serve as potential therapeutic targets for treatment of IBS and other functional bowel disorders.

Public Health Relevance

The focus of my research is on how adverse events during neonatal development can permanently alter pain processing in adulthood. As neonatal care improves, early gestational-age infant survival rates are increasing. However, these premature infants can spend weeks or months in the neonatal care unit where they are subjected to adverse conditions, both in terms of stress from maternal separation and from the multiple painful interventions required on a daily basis. The experiments included in this proposal will address neonatal stress- related outcomes in visceral pain processing, in terms of colon sensitivity, the expression of pain-related molecules on neurons innervating the colon and susceptibility to future colon insult (inflammation).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK088011-01
Application #
7875043
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2010-04-01
Project End
2010-06-30
Budget Start
2010-04-01
Budget End
2010-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$8,490
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Fuentes, Isabella M; Walker, Natalie K; Pierce, Angela N et al. (2016) Neonatal maternal separation increases susceptibility to experimental colitis and acute stress exposure in male mice. IBRO Rep 1:10-18
Pierce, Angela N; Zhang, Zhen; Fuentes, Isabella M et al. (2015) Neonatal vaginal irritation results in long-term visceral and somatic hypersensitivity and increased hypothalamic-pituitary-adrenal axis output in female mice. Pain 156:2021-31
Fuentes, Isabella M; Pierce, Angela N; O'Neil, Pierce T et al. (2015) Assessment of Perigenital Sensitivity and Prostatic Mast Cell Activation in a Mouse Model of Neonatal Maternal Separation. J Vis Exp :e53181
Pierce, A N; Ryals, J M; Wang, R et al. (2014) Vaginal hypersensitivity and hypothalamic-pituitary-adrenal axis dysfunction as a result of neonatal maternal separation in female mice. Neuroscience 263:216-30
Schwartz, Erica S; Christianson, Julie A; Chen, Xiaowei et al. (2011) Synergistic role of TRPV1 and TRPA1 in pancreatic pain and inflammation. Gastroenterology 140:1283-1291.e1-2
Christianson, Julie A; Bielefeldt, Klaus; Malin, Sacha A et al. (2010) Neonatal colon insult alters growth factor expression and TRPA1 responses in adult mice. Pain 151:540-9