Visceral Afferents

Inflammatory Bowel Diseases

pain, nociceptor, sensitization

The vast majority of what is known about the extrinsic innervation of the visceral was obtained through the study of preclinical models, primarily rats and mice. Given a growing list of important species differences, the investigators wish to determine the extent to which what scientists think they know about the control of visceral afferent excitability learned through the study of rodents holds true for humans. The investigators wish to establish an ex-vivo preparation using intestine surgically removed for the treatment of cancer, ischemia, etc, that would normally be disposed of as medical waste, to study the properties of the extrinsic innervation of the intestine. Tissue will be recovered in the OR, taken back to the lab, and evoked activity in the neurons innervating the intestine will be studied with extracellular recording techniques. Pharmacological approaches will be used to characterize the ion channels/receptors controlling the excitability of visceral afferents. After recording, tissue may be further analyzed with biochemical approaches such as western blot, PCR, and/or flow cytometry.

Visceral pain disorders such as irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD; Crohn's disease, ulcerative colitis) remain a significant health problem both because of the large number of people who suffer from these disorders and because there are few, if any consistently effective therapeutic interventions. Thus, the goal of this project is to identify novel therapeutic approaches for the treatment of visceral pain. The sensation of visceral pain is transmitted from visceral structures to the central nervous system via sensory neurons where the increase in pain associated with IBS and IBD is due, at least in part to increases in the excitability of these sensory neurons. Virtually all that scientists know about visceral sensory neurons was learned through the study of non-human species, in particular, rats and mice. A growing body of evidence suggests that many of the discoveries made in these species have failed to translate into more effective treatments because of species differences. To address this gap in knowledge, the investigators have proposed to study human tissue. Based on the investigator's preclinical data, they will start with a focus on GABA receptors, but will also explore other ionotropic receptors (for serotonin and ATP), as well as voltage gated ion channels. The investigators hypothesize that the dearth of effective treatments for visceral pain is due, at least in part, to species differences in the channels controlling the excitability of visceral sensory neurons. Electrophysiological techniques combined with pharmacological approaches will be used for a functional analysis of visceral afferents, and these endpoints will be complimented by biochemical, anatomical, and molecular biological analyses. Electrophysiological analysis of tissue will be performed on the day of surgery. Tissue will be processed and stored for biochemical, anatomical, and molecular biological analyses on the day of surgery, but analyzed once per month if it is possible to recover tissue from two patients per week.

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United States