Knowledge Bank

The endogenous opioid peptides, including enkephalin, endorphin, and dynorphin, are important for regulating gut motility. Pharmaceutical drugs that target opioid receptors have been developed to treat functional gastrointestinal disorders such as irritable bowel diseases. However, the cellular sources from which endogenous opioid peptides are secreted in the gastrointestinal system remain incompletely understood. Previous studies have shown that a group of specialized sensory cells in the intestine epithelium called enteroendocrine cells (EECs) synthesize and secrete the endogenous opioid peptide enkephalin. Whether and how EEC enkephalin signaling regulates enteric neuron activity to control gut motility remains unknown. Our recent study demonstrates that like mammals, a subset of EECs in the small intestine of zebrafish secretes enkephalin. Here, we characterized a new zebrafish genetic model in which the pre-proenkephalin A (penka) gene is mutated and leads to loss of enkephalin secretion in EECs. Loss of EEC enkephalin signaling did not alter larvae zebrafish development and body length. However, penka-/- zebrafish displayed body shape abnormality and inflamed red gills at 10 months old. To determine whether and how EEC enkephalin signaling affects enteric neuron activity, we developed a novel 3D segmentation and tracking method to track individual enteric neuronal calcium activity in a spatiotemporal manner. Our data reveals that at the basal level, a subset of enteric neurons undergo spontaneous calcium firing. Loss of enkephalin signaling did not change the enteric neuron calcium amplitude but altered the ENS firing patterns. These results suggest that EECs may secrete enkephalin at the basal level to regulate ENS neuronal activity. Selectively targeting EEC enkephalin signaling may open new opportunities to treat functional GI disorders that display abnormal gut motilities.