Dynorphin A Inhibits Insulin Secretion Through Opioid Receptor–Dependent Modulation of β-Cell Ca2+ Dynamics

Opioids are classically associated with pain and reward; however, endogenous opioid peptides and their receptors are also expressed in pancreatic islets, where their physiologic role remains unclear. Building on evidence indicating that β-cells corelease dynorphin A with insulin, we show that applied dynorphin A inhibits insulin secretion during glucose stimulation. Dynorphin A dose-dependently suppresses glucose-stimulated insulin secretion in mouse and human islets while preserving insulin content and β-cell viability. Under dynamic perifusion, dynorphin A attenuates both first- and second-phase insulin release. Mechanistically, dynorphin A slows glucose-stimulated β-cell Ca2+ oscillations in pancreatic slices, reducing oscillatory frequency while prolonging individual Ca2+ events. Notably, the receptor requirements for the inhibitory response to applied dynorphin A differ across species; μ-opioid receptor blockade or β-cell–specific deletion abolishes inhibition in mouse islets, whereas δ-opioid receptor antagonism prevents dynorphin A–mediated inhibition in human islets. These findings define the opioid receptor mechanisms underlying the inhibitory response to applied dynorphin A and reveal species-dependent receptor involvement in mouse and human islets.