Gastric dysreflexia after spinal cord injury

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): The most apparent consequence of spinal cord injury (SCI) is the immediate loss of sensation and motor function. However, a dramatic impairment of the functionality of the gastrointestinal (GI) tract occurs in the vast majority of the patients, many of whom have a severely depressed gastric motility that necessitates enteral feeding. The pathophysiology of these disorders remains incompletely understood, but data gathered during the previous funding period point toward diminished responsiveness of vagal afferent signaling from the GI tract to the nucleus tractus solitarius (NTS) in the medulla. For example, SCI results in 1) diminished postprandial serum expression of cholecystokinin (CCK); 2) diminished NTS activation following peripheral sulfated CCK (CCK-8s); 3) diminished gastroinhibition following central microinjection of CCK-8s into the NTS; and 4) diminished in vitro, whole cell recordings of excitatory post-synaptic currents following bath application of CCK-8s. A subclass of NTS neurons provide a tonic inhibitory (GABA) input onto motoneurones of the dorsal motor nucleus of the vagus (DMV), which composes the vagal motor limb of vago-vagal GI reflexes. Our novel pilot data have identified similar derangements to the prokinetic GI peptide, ghrelin. We hypothesize that a post-SCI reduction in afferent signaling within the gut-brain axis may bias NTS-DMV activity in favor of an inhibitory GABAergic resting tone. This unopposed inhibitory signal may be one mechanism leading to GI dysmotility following SCI. While clinical interest in the therapeutic potential of ghrelin is emerging, the therapeutic efficacy of ghrelin mimetics may be diminished for use in SCI patients. In the present proposal we will use an animal model of T3-SCI combined with in vivo physiological (gastric emptying or motility and vagus nerve) recording, and molecular (RT-PCR and ELISA) approaches with the aim of defining the mechanisms resulting in the loss of GI function after SCI. Our overarching hypothesis is that spinal cord injury reduces vagal afferent signaling and provokes gastric dysmotility through unregulated GABAergic signaling within brainstem vagal circuits. Specifically we will test the hypotheses that 1) reduced vagal afferent signaling to gastric brainstem circuits is mediated by diminished GI peptide release; 2) reduced presynaptic glutamatergic signaling within gastric brainstem circuits is mediated by reduced sensitivity of vagal afferents to GI peptides; 3) reduced vagal afferent and NTS neuronal sensitivity to feeding-related peptides biases GI brainstem circuits toward a tonic GABAergic inhibition of DMV efferent outflow to the stomach. The data generated by the present proposal will provide novel information regarding the efficacy of therapeutic strategies to reduce GI dysmotility following SCI, thereby improving functional outcome of digestive processes. This proposal will provide the basis to refine a model of post-SCI alterations in gastrointestinal function that encompasses the entire length of the GI tract. Ultimately this will help alleviate GI dysfunctions in SCI patients.
StatusFinished
Effective start/end date4/1/063/31/19

Funding

  • National Institute of Neurological Disorders and Stroke: $289,043.00
  • National Institute of Neurological Disorders and Stroke: $297,675.00
  • National Institute of Neurological Disorders and Stroke: $289,043.00
  • National Institute of Neurological Disorders and Stroke: $180,970.00
  • National Institute of Neurological Disorders and Stroke: $336,346.00
  • National Institute of Neurological Disorders and Stroke: $324,527.00
  • National Institute of Neurological Disorders and Stroke: $325,387.00
  • National Institute of Neurological Disorders and Stroke: $105,183.00
  • National Institute of Neurological Disorders and Stroke: $289,043.00
  • National Institute of Neurological Disorders and Stroke: $332,884.00
  • National Institute of Neurological Disorders and Stroke: $336,195.00

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.