Mechanism of Action
Motilin Receptor (MLNR) Signaling
Motilin binds MLNR, a Gq-coupled GPCR expressed in gastric and small intestinal smooth muscle and in enteric cholinergic neurons. Receptor activation increases intracellular IP3 and calcium, causing smooth muscle contraction and initiating the phase III MMC contraction front. In enteric neurons, MLNR activation enhances cholinergic input to smooth muscle, amplifying contraction propagation throughout the small intestine.
Gastric Emptying and Prokinesis
Beyond the interdigestive MMC, supraphysiological motilin concentrations accelerate gastric emptying of both solids and liquids. This gastric prokinetic effect is the pharmacological basis for erythromycin and newer motilin agonist drugs in treating gastroparesis and other gastric emptying disorders. Unlike metoclopramide (dopamine antagonist), motilin agonists do not affect the CNS dopamine system.
Research Summary
Gastroparesis
HumanIV and oral erythromycin (motilin agonist) accelerates gastric emptying in diabetic and idiopathic gastroparesis patients. However, tachyphylaxis (tolerance) develops within days with continuous erythromycin use, limiting long-term utility. Non-antibiotic motilin agonists with improved receptor selectivity and reduced tolerance (camicinal, atilmotin) have been evaluated in Phase II trials for gastroparesis and constipation.
Postoperative Ileus
HumanMotilin infusion has been evaluated for resolution of postoperative ileus following abdominal surgery. Early studies showed accelerated return of bowel function, but larger confirmatory trials produced inconsistent results. Motilin agonists for postoperative GI recovery remain an active research area.
Critical Care GI Motility
HumanCritically ill patients frequently develop GI dysmotility. Erythromycin as a motilin agonist improves gastric emptying in ICU patients on enteral nutrition, reducing aspiration risk and improving nutritional delivery. This represents the most established current clinical application of motilin receptor agonism.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Gastroparesis research | 1-3 mcg/kg | IV infusion or 3x daily SC | IV or subcutaneous |
| ICU prokinesis | 250 mg erythromycin (motilin agonist) | q6-8h IV | Intravenous (erythromycin surrogate) |
Native motilin has a very short half-life. Clinical prokinetic use typically employs erythromycin or investigational non-antibiotic motilin agonists rather than native motilin peptide.
Interactions
Safety Profile
Native motilin infusion in humans produces expected GI effects including abdominal cramping, urgency to defecate, and nausea at higher doses. These are pharmacologically predictable GI smooth muscle effects. Erythromycin as a motilin agonist carries the risk of QT prolongation and drug interactions typical of macrolides. Non-antibiotic motilin agonists in development have shown more favorable safety profiles.
References
- [1]Brown JC, et al. Identification and actions of motilin. Can J Physiol Pharmacol. 1971.
- [2]Tack J, et al. Motilin receptor agonists for gastroparesis. Neurogastroenterol Motil. 2012.
- [3]Broad J, Sanger GJ. The antibiotic azithromycin is a motilin receptor agonist in human stomach. Br J Pharmacol. 2013.