GIP receptor agonism blocks chemotherapy-induced nausea and vomiting

• Published in: Molecular metabolism (Germany) Vol. 73; p. 101743
• Main Authors: Borner, Tito, Reiner, Benjamin C., Crist, Richard C., Furst, C. Daniel, Doebley, Sarah A., Halas, Julia G., Ai, Minrong, Samms, Ricardo J., De Jonghe, Bart C., Hayes, Matthew R.
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01-07-2023; Elsevier
• Subjects: Animals; Antiemetic; Antineoplastic Agents - adverse effects; Chemotherapy; Cisplatin - adverse effects; Diabetes; Ferrets; Incretin; Nausea - chemically induced; Nausea - drug therapy; Nausea - epidemiology; Obesity; Original; Rats; Vomiting; Vomiting - chemically induced; Vomiting - drug therapy; Incretin; Obesity; Chemotherapy; Diabetes; Vomiting; Antiemetic
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2023.101743

Nausea and vomiting remain life-threatening obstacles to successful treatment of chronic diseases, despite a cadre of available antiemetic medications. Our inability to effectively control chemotherapy-induced nausea and vomiting (CINV) highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that block CINV.
Behavioral pharmacology assays of nausea and emesis in 3 different mammalian species were combined with histological and unbiased transcriptomic analyses to investigate the beneficial effects of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism on CINV.
Single-nuclei transcriptomics and histological approaches in rats revealed a topographical, molecularly distinct, GABA-ergic neuronal population in the dorsal vagal complex (DVC) that is modulated by chemotherapy but rescued by GIPR agonism. Activation of DVCGIPR neurons substantially decreased behaviors indicative of malaise in cisplatin-treated rats. Strikingly, GIPR agonism blocks cisplatin-induced emesis in both ferrets and shrews.
Our multispecies study defines a peptidergic system that represents a novel therapeutic target for the management of CINV, and potentially other drivers of nausea/emesis.
•GIPR agonism attenuates cisplatin-induced emesis in ferrets and shrews.•Activation of hindbrain GIPR + neurons decreases malaise in cisplatin-treated rats.•Cisplatin induces profound transcriptomic alternations in hindbrain GABAergic neurons.•GIPR agonism may exert its anti-emetic actions by restoring GABA-ergic activity.•The GIPR system represents a novel therapeutic target for the management of CINV.