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

Abstract

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. Article Highlights The role of endogenous opioid signaling within pancreatic islets remains poorly defined. We investigated whether dynorphin A regulates insulin secretion and characterized the receptor requirements for the acute response to applied dynorphin A in mouse and human islets. Applied dynorphin A suppressed glucose-stimulated insulin secretion by remodeling β-cell Ca2+ oscillations through an opioid receptor–dependent, Na+/K+-ATPase–associated pathway. This response required μ-opioid receptors in mouse β-cells and was pharmacologically consistent with δ-opioid receptor involvement in human islets, defining species-dependent receptor mechanisms for the acute response to dynorphin A.