Central Mechanisms Involved In The Erythromycin Enhancement Of Gastric Motility

[Background and Purpose]Erythromycin is one of the major macrolide antibiotics widely used for anti-mycoplasma and Chlamydia. Due to its severe gastrointestinal reaction such as nausea and vomiting is clinical application is limited. On the other hand, this indicates that erythromycin play an important role in gastric motility regulation. In 1984, the UK scholar Pilot observed that erythromycin could promote gastric motility, in the same year Japanese scholars Itoh reported that erythromycin could induce a new MMC (Migrating Myoelectrical Complex) at a small dosage. In 1986, XinYu Qin confirmed that large doses of erythromycin could increase the number of small intestinal quick wave in satiety or fasting dogs, which suggests that erythromycin plays an important role in the promotion of gastrointestinal motility. In the past 15 years, erythromycin has been gradually become a cure of gastrointestinal motility disorders clinically.Erythromycin has been certified as the agonist of motilin receptors. The peripheral prokinetic mechanism is probably via its action on the acetylcholine neurons or on motilin receptors, which results in smooth muscle contraction via increasing the release of acetylcholine and increasing intracellular calcium. Furthermore, erythromycin can pass through the blood-brain barrier:motilin receptor can be detected in the central nerval system in mammals. Micro-injection of erythromycin in the central system could enhance gastric motility and change the discharge activity of neurons. All these prokinetic activities indicte some central mechanisms related to the vagus nerve. However, the sites of action and the precise mechanism is still not known. Gastric preganglionic vagus nerve fibers mainly originate from Dorsal Motor Nucleus of the Vagus in the medulla oblongata, and gastric vagal preganglionic neurons receive not only modulation of acetylcholine, but also glutamatergic, GABAergic and glycinergic presynaptic inputs.However, little is known about whether and how erythromycin promotes gastric motility via its action on gastric vagal preganglionic neurons. Using patch-clamp techniques this study investigates the effect of erythromycin on the synaptic inputs of gastric-vagal preganglionic neurons at the synaptic level.[Aims]1. The distribution of gastric-vagal preganglionic neurons in the medulla oblongata.2. The effect of erythromycin on the synaptic inputs of inhibitory and excitatory postsynaptic currents on gastric-vagal preganglionic neurons.3. The specificity of the effects of erythromycin on gastric-vagal preganglionic neurons.[Methods]1. Brain slice preparation of rat medulla oblongata.2 Retrograde fluorescent labeling of rat gastric-vagal preganglionic neurons.3. The identification, recording of presynaptic activity and neuropharmacological isolation of rat gastric-vagal preganglionic neurons, cardiac vagal preganglionic neurons and airway-related parasympathetic (vagal) preganglionic neurons.[Results]1. Tracer rhodamine application directly to the gastric wall labeled the putative gastric-vagal preganglionic neurons within the dorsal motor nucleus of the vagus. While tracer application to the pericardium or to the tracheal wall labeled the putative CVPNs (cardiac vagal parasympathetic preganglionic neurons)within the compact portion of the nucleus ambiguous (cNA)or the APPNs (airway-related parasympathetic preganglionic neurons) in the ventrolateral portion of the NA.2. Erythromycin inhibits the spontaneous and miniature glycinergic inhibi tory postsynaptic currents of gastric-vagal preganglionic neurons, and has no influence on the spontaneous GABAergic inhibitory postsynaptic currents. 3. Erythromycin does not influence the spontaneous glycinergic inhibitory postsynaptic currents of the putative CVPNs or the APPNs.4. Motilin receptor antagonist GM109 at the same dose blocked the effects of erythromycin on the glycinergic spontaneous inhibitory postsynaptic currents (sIPSCs). GM109 itself had no effect on these currents.[Conclusions]1. Tracer rhodamine application directly to the gastric wall labeled the putative gastric-vagal preganglionic neurons within the dorsal motor nucleus of the vagus.2. Erythromycin inhibits the glycinergic inputs of gastric vagal preganglionic neurons, and has no influence on the GABAergic inputs. This action is presynaptic and action-potential independent.3. Erythromycin indirectly excited the preganglionic gastric vagal neurons via inhibition of their glycinergic inputs. This may be the erythromycin prokinetic mechanism.4. Erythromycin does not influence the spontaneous glycinergic inhibitory postsynaptic currents of the putative CVPNs or the APPNs, which proves the specificity of the effects of erythromycin on the glycinergic synaptic inputs of gastric preganglionic vagal motor neurons in the medulla oblongata.5. The effects of GM109 prompted that erythromycin prokinetic mechanism possibly involves motilin receptors on the presynaptic terminal membrane of glycinergic neurons projecting to gastric preganglionic vagal motor neurons.