Childhood functional abdominal pain (CFAP) is present in about 8% to 38% of 4- to 14-year-old children and abdominal pain is a prominent symptom in irritable bowel syndrome (IBS), comprising 10% to 15% of the U.S. population. CFAP adversely affects academic performance and the family socioeconomic conditions. Clinical studies have noted that female patients report more frequent and greater pain morbidity than male patients. Clinical studies have identified visceral hypersensitivity (VHS) as an important contributor to visceral pain. Cellular investigations in affected tissues are required to advance the field, but visceral tissues are seldom available from human subjects. However, Retrospective studies have identified that severe psychological stress caused by early life trauma is a risk factor for the development of symptoms CFAP and IBS patients. Preclinical animal models are essential to identifying the cellular mechanisms of VHS. Preclinical studies in rodents show that neonatal colon irritation or maternal separation can influence the development of VHS in later life. However, epigenetic programming is more sensitive to the cellular microenvironment during fetal than during neonatal development. In this regard, our proposal will advance the field by investigating the cellular and epigenetic mechanisms by which chronic prenatal stress (CPS) induces sexually dimorphic VHS in adult and peripubertal offspring. We will test the hypothesis that the development of VHS in response to chronic prenatal stress is a two-step process: exposure to robust CPS followed by exposure to robust chronic stress in later life. CPS activates the neuroendocrine axis to trigger 1) fetal programming of such neurotrophins as brain-derived neurotrophic factor and nerve growth factor, and their receptors trkB and trkA respectively in the spinal cord; and 2) serotonin synthesis enzymes in the CNS to induce sexually dimorphic VHS in the offspring. Chronic adult stress (CAS) or chronic peripubertal stress (CPPS) in female offspring subjected to previous CPS triggers an interaction between spinal cord estrogen and serotonin to epigenetically upregulate the expression of select neurotrophins to aggravate and prolong VHS.
The specific aims are to investigate: 1) the neurohormonal and cellular mechanisms by which chronic prenatal stress induces sexually dimorphic visceral hypersensitivity, when subjected to CPPS, and/or 2) the cellular and epigenetic mechanisms of interactions between the sex steroid hormone estrogen and serotonin in the spinal cord that aggravate visceral hypersensitivity in female rats subjected to chronic prenatal stress followed by chronic peripubertal and/or chronic adult stress.
Irritable bowel syndrome patients report severe abdominal pain associated with altered bowel habits, symptoms that are more frequent and severe in women. We hypothesize that severe psychological stress during pregnancy followed by stressful experiences during childhood and/or adult life cumulatively make people, females more than males, susceptible to develop these symptoms as adults by altering the way the spinal cord processes sensory information from the colon. In our rat model, we will determine whether these alterations include increases in a specific neurotrophin signaling molecules and serotonin and its receptors in the spinal cord; our results should lead to new and better therapies for functional dyspepsia.
