Fecal incontinence and fecal urgency (FI/FU) are extremely inconvenient and stigmatizing conditions that are common in the elderly, nursing home residents, women (due to anal damage during childbirth), and people with neurological conditions (e.g. spinal injury, multiple sclerosis). It is especially high in elderly with age-related dementia. The severe impacts of FI make at-home care difficult, and patients and caregivers suffer the emotional burdens of shame, embarrassment, and stigmatism. FI is associated with declining mental health and increased risk for psychological distress and depressive symptoms. Thus, incontinence is one of the top reasons for institutionalization of the elderly, and nearly 50% of all nursing home residents, and 66% of those with age-related dementia, exhibit FI. Current management of FI for most patients at home and in institutions is to simply prevent a mess when an FI “accident” occurs (i.e. wearing adult diapers to catch the stool) and trying to normalize GI function (e.g. treat diarrhea or constipation). Wearing a diaper does not prevent the odors of the stool from broadcasting that FI has occurred (which can hinder professional and social relationships), and relieving constipation or diarrhea is only effective in 1 of 5 patients. Clinical and preclinical evidence indicates FI/FU can result from sensitization of a specific population of colorectal afferent terminals. Dignify proposes that inhibiting these colorectal afferent terminals will safely and effectively prevent or reduce the symptoms of FI/FU, as well as reduce symptoms of pain and discomfort associated with irritable bowel syndrome (IBS). Colorectal sensory fibers will be inhibited by intrarectal administration of proprietary compounds that are known to inhibit sensitized afferent terminals in other regions of the body and produce analgesia. An important advantage of local, intrarectal administration of the compounds is elimination or reduction of systemic distribution of the compounds, which reduces the possibility of off-target side-effects. Specific Aim 1 examines the effects of the compounds on colorectal function and establishes the duration of colorectal afferent inhibition to guide dosing frequency. Our phase 2 SBIR plans are to test the “best” compound in a translational model of FI in TNBS-treated rats, optimize a suppository formulation, initiate IND-enabling studies, and immunohistochemically examine the effects of the analgesics on phenotypically-identified rectal afferent fibers of treated animals to provide insight regarding mechanism of action.