GHRP-2 inhibits postprandial gut contractions and boosts food intake via distinct neural pathways in dogs
Background
Upper gastrointestinal motility disorders and appetite dysregulation represent significant clinical challenges where understanding the role of gut-brain signaling is essential. GHRP-2 is a synthetic ligand for the growth hormone secretagogue receptor (GHSR), a receptor also activated by the endogenous orexigenic peptide ghrelin. While GHSR agonists are known to stimulate growth hormone release, their effects on gastrointestinal contractile activity and food intake are incompletely characterized. Understanding how GHRP-2 modulates both enteric and vagal pathways could clarify the dual gut-motor and appetite-regulatory functions of the ghrelin receptor system, which is relevant to conditions such as gastroparesis, cachexia, and functional dyspepsia.
Study Design
GHRP-2 (0.5–10 µg/kg) was administered intravenously to two groups of conscious dogs: five neurally intact dogs and five dogs with vagotomy and pyloroplasty. Strain gauge force transducers were surgically placed on the stomach, duodenum, and jejunum to measure contractile activity. Experiments were conducted in both the interdigestive state and after feeding. To probe mechanism, various adrenergic antagonists (alpha- and alpha2-blockers) were administered intravenously prior to GHRP-2. Food intake was assessed after GHRP-2 administration immediately before feeding in both groups.
Results
GHRP-2 produced no gastrointestinal contractions during the interdigestive state in either group. In the postprandial period, GHRP-2 induced contractile inhibition lasting 2–3 minutes in both neurally intact dogs and dogs with vagotomy, indicating this effect does not require an intact vagal nerve. The inhibitory effect on postprandial contractions was reversed by alpha- and alpha2-adrenergic receptor blockers, implicating alpha2-receptors on the enteric nervous system as the primary mediators.
The most striking dissociation: GHRP-2 increased food intake only in neurally intact dogs, with no orexigenic effect observed in vagotomized animals — demonstrating that vagal integrity is essential for GHRP-2-driven appetite stimulation but not for its motor-inhibitory action.
Together, these results reveal a mechanistic split: gut motor inhibition is peripherally mediated via enteric alpha2-receptors, while the food-intake-promoting effect requires intact central-vagal communication.
Key Findings
- GHRP-2 caused no GI contractions in the interdigestive (fasted) state at any dose tested.
- Postprandial contractile inhibition lasted 2–3 minutes and occurred in both intact and vagotomized dogs.
- Alpha- and alpha2-adrenergic blockers reversed GHRP-2-induced contractile inhibition, implicating enteric alpha2-receptors.
- GHRP-2 increased food intake in neurally intact dogs but produced no orexigenic effect in vagotomized dogs.
- Vagal nerve integrity is necessary for GHRP-2-induced appetite stimulation but not for motor inhibition.
Why It Matters
The dissociation between GHRP-2's motor-inhibitory and appetite-stimulating effects has direct implications for clinical use. For practitioners or researchers considering GHRP-2 in protocols targeting appetite or body composition, the data suggest that vagal nerve integrity is a prerequisite for orexigenic response — patients with vagal dysfunction (e.g., post-surgical, diabetic autonomic neuropathy) may not experience appetite benefits. Conversely, the transient alpha2-mediated postprandial contractile inhibition is vagus-independent and could influence GI tolerability or motility-related side effects regardless of vagal status. Stacking GHRP-2 with prokinetic agents or timing doses relative to meals deserves further study given this inhibitory motor window of 2–3 minutes post-administration. Full clinical translation remains distant — this is a canine surgical model with no human pharmacokinetic or safety data presented.
