Ghrelin inhibits autonomic gastric distension response by acting on vagal pathway neurons
Background
Ghrelin, widely known as the primary orexigenic (hunger-stimulating) peptide, also functions as a potent prokinetic agent, enhancing gastric motility. However, emerging research suggests its physiological role is much broader than satiety regulation alone. While previous studies have established ghrelin's ability to provide antinociception (pain relief) in somatic tissues and the colon, its specific impact on gastric sensitivity has remained an open question. This is particularly relevant as the stomach itself is a major source of ghrelin secretion. Understanding how ghrelin modulates sensory feedback from the stomach could reveal new therapeutic avenues for disorders involving gastric discomfort and mechanosensitivity.
Study Design
This study used rats to investigate ghrelin's effect on gastric mechanosensitivity. The primary endpoint was the autonomic response to gastric distension (GD), measured via changes in blood pressure. To determine the neural pathways involved, researchers performed surgical interventions: celiac ganglionectomy to assess the spinal pathway and subdiaphragmatic vagotomy for the vagal pathway. Neuronal activation was quantified by measuring phosphorylated extracellular-regulated kinase 1/2 (p-ERK1/2) expression in dorsal root and nodose ganglia. The specific role of the ghrelin receptor was confirmed by pre-treating rats with the antagonist [D-Lys3]-GHRP-6 (0.3 mg/kg i.v.) before ghrelin administration. Finally, in situ hybridization and immunofluorescence were used to identify the phenotype of ghrelin receptor-expressing neurons in the nodose ganglia.
Results
Ghrelin administration significantly reduced the blood pressure variation that normally occurs in response to gastric distension (GD), indicating a decrease in gastric mechanosensitivity. This inhibitory effect was completely absent in rats that had undergone vagotomy, but was unaffected by celiac ganglionectomy, pinpointing the vagal pathway as the critical mediator. Analysis of neuronal markers supported this, showing that ghrelin reduced the GD-induced increase in p-ERK1/2 levels specifically in the nodose ganglion (part of the vagal pathway), but not the dorsal root ganglion (spinal pathway).
The ghrelin-induced reduction in gastric mechanosensitivity was entirely abolished by pre-treatment with the Ghrelin receptor antagonist [D-Lys3]-GHRP-6. Furthermore, immunofluorescence staining revealed that the Ghrelin receptor (
GHSR) is co-localized with the sensory ion channelsASIC3andTRPV1within the gastric neurons of the nodose ganglion. This co-localization provides a direct cellular mechanism for ghrelin's modulatory effect on gastric sensory signaling.
Key Findings
- Ghrelin administration reduced blood pressure variation in response to gastric distension (GD) in rats.
- The effect of ghrelin on gastric mechanosensitivity was abolished by pre-treatment with the antagonist [D-Lys3]-GHRP-6 (0.3 mg/kg i.v.).
- Ghrelin's effect was absent in vagotomized rats, indicating mediation via the vagal pathway.
- Ghrelin reduced GD-induced neuronal activation (p-ERK1/2 levels) in the nodose ganglion, but not the dorsal root ganglion.
- Ghrelin receptors co-localize with ASIC3 and TRPV1 ion channels on gastric neurons of the nodose ganglion.
Why It Matters
This research clarifies a novel function for ghrelin beyond hunger stimulation, establishing it as a key modulator of gastric sensory feedback. For individuals using ghrelin mimetics or GH secretagogues, this suggests a potential side effect or benefit related to reduced stomach discomfort or altered feelings of fullness. The finding that ghrelin acts on vagal neurons co-expressing TRPV1 and ASIC3 opens up new therapeutic possibilities for functional gastrointestinal disorders characterized by visceral hypersensitivity, like functional dyspepsia. This mechanism suggests that targeting the ghrelin system could be a viable strategy for managing gastric pain and discomfort. However, this is preclinical animal data; clinical translation would require human trials to determine effective dosing, safety, and efficacy for gastric sensory disorders. It also implies that the timing of ghrelin-agonist administration relative to meals could influence gastric sensations.
