Diminished gastric prokinetic response to ghrelin in a rat model of spinal cord injury

Abstract

Background

Patients with cervical or high-thoracic spinal cord injury (SCI) often present reduced gastric emptying and early satiety. Ghrelin provokes motility via gastric vagal neurocircuitry and ghrelin receptor agonists offer a therapeutic option for gastroparesis. We have previously shown that experimental high-thoracic injury (T3-SCI) diminishes sensitivity to another gastrointestinal peptide, cholecystokinin. This study tests the hypothesis that T3-SCI impairs the vagally mediated response to ghrelin.

Methods

We investigated ghrelin sensitivity in control and T3-SCI rats at 3-days or 3-weeks after injury utilizing: (i) acute (3-day post-injury) fasting and post-prandial serum levels of ghrelin; (ii) in vivo gastric reflex recording following intravenous or central brainstem ghrelin; and (iii) in vitro whole cell recording of neurons within the dorsal motor nucleus of the vagus (DMV).

Key Results

The 2-day food intake of T3-SCI rats was reduced while fasting serum ghrelin levels were higher than in controls. Intravenous and fourth ventricle ghrelin increased in vivo gastric motility in fasted 3-day control rats but not fasted T3-SCI rats. In vitro recording of DMV neurons from 3-day T3-SCI rats were insensitive to exogenous ghrelin. For each measure, vagal responses returned after 3-weeks.

Conclusions and Inferences

Hypophagia accompanying T3-SCI produces a significant and physiologically appropriate elevation in serum ghrelin levels. However, higher ghrelin levels did not translate into increased gastric motility in the acute stage of T3-SCI. We propose that this may reflect diminished sensitivity of peripheral vagal afferents to ghrelin or a reduction in the responsiveness of medullary gastric vagal neurocircuitry following T3-SCI.

Brainstem gastric neurocircuitry remains anatomically intact after spinal cord injury (SCI), however, our previous studies suggest that activation of the afferent vagus is compromised in the days to weeks after injury. In a rodent model of SCI, the aim of the present report was to investigate the sensitivity of vagally mediated gastric contractions to ghrelin. Using in vivo and in vitro neuropharmacological techniques, this study demonstrates that ghrelin sensitivity is blunted in the acute stages of SCI but returns to near-normal in the chronic recovery stage of SCI.

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