Clinical trial NCT04794335: Visceral Afferents
Official title: Pharmacology of Visceral Afferents
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: Inflammatory Bowel Diseases
Keywords: pain
nociceptor
sensitization
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2021-03-12
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All subjects (\>18), younger than 85, scheduled for abdominal surgery involving the removal of GI tissue for therapeutic purposes.

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* This study's inclusion criteria are fairly straightforward: an adult (\>18), younger than 85
* Scheduled for abdominal surgery involving the removal of GI tissue for therapeutic purposes
* Meets ASA 1-3 criteria.

Exclusion Criteria:

* Subject \<18 years of age.
* Subject declines participation.

Primary outcomes:
measure: Single unit activity in afferents innervating intestine specimen
timeFrame: The presence of activity will be assessed immediately in each specimen recovered, day 1 of surgery.
measure: The ability to identify receptive fields of visceral afferents in the intestine
timeFrame: The presence of receptive fields will be assessed immediately in each specimen recovered, day 1 of surgery.
measure: Pharmacological characterization of isolated visceral afferent
timeFrame: Pharmacological analysis will be performed immediately on each specimen recovered day 1 of surgery.
measure: Changes in threshold of action potential generation in response to inflammatory mediators and/or GABAA agonists or agonist/antagonist combinations.
timeFrame: Excitability will be analyzed immediately on each specimen recovered, day 1 of surgery.
Secondary outcomes:
measure: Biochemical characterization of GABAA receptor signaling molecules in human intestine
timeFrame: Tissue for biochemical analysis will be flash frozen on day 1 of surgery.
measure: Anatomical characterization of GABAA receptor signaling molecules in human intestine
timeFrame: Tissue for anatomical analysis will be immersion fixed on day 1 of surgery.
measure: Molecular biological characterization of GABAA receptor signaling molecules in human intestine
timeFrame: Tissue for molecular biological analysis will be flash frozen on day 1 of surgery.
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center (UPMC) Presbyterian
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Michael S Gold, PhD
role: PRINCIPAL_INVESTIGATOR
References: