Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea

• Cisplatin chemotherapy activates central GLP-1-producing neurons in the NTS.
• Blockade of hindbrain GLP-1 receptors attenuates cisplatin induced delayed anorexia.
• Blockade of hindbrain GLP-1 receptors attenuates cisplatin induced delayed pica.
• Hindbrain GLP-1 receptor blockade attenuates cisplatin induced body weight loss.

While chemotherapy-induced nausea and vomiting are clinically controlled in the acute (< 24 h) phase following treatment, the anorexia, nausea, fatigue, and other illness-type behaviors during the delayed phase (> 24 h) of chemotherapy are largely uncontrolled. As the hindbrain glucagon-like peptide-1 (GLP-1) system contributes to energy balance and mediates aversive and stressful stimuli, here we examine the hypothesis that hindbrain GLP-1 signaling mediates aspects of chemotherapy-induced nausea and reductions in feeding behavior in rats. Specifically, hindbrain GLP-1 receptor (GLP-1R) blockade, via 4th intracerebroventricular (ICV) exendin-(9-39) injections, attenuates the anorexia, body weight reduction, and pica (nausea-induced ingestion of kaolin clay) elicited by cisplatin chemotherapy during the delayed phase (48 h) of chemotherapy-induced nausea. Additionally, the present data provide evidence that the central GLP-1-producing preproglucagon neurons in the nucleus tractus solitarius (NTS) of the caudal brainstem are activated by cisplatin during the delayed phase of chemotherapy-induced nausea, as cisplatin led to a significant increase in c-Fos immunoreactivity in NTS GLP-1-immunoreactive neurons. These data support a growing body of literature suggesting that the central GLP-1 system may be a potential pharmaceutical target for adjunct anti-emetics used to treat the delayed-phase of nausea and emesis, anorexia, and body weight loss that accompany chemotherapy treatments.