Abstract
The most common side effects of cisplatin chemotherapy are nausea and vomiting, and the overwhelming majority of research studies on the mechanism of cisplatin-induced nausea have been focused on the “vomiting center.” As a modulatory center of gastric motility, the roles of the hypothalamus in nausea and vomiting remain unclear. In the present study, we investigated the effects of exogenous orexin-A injected into the arcuate nucleus (ARC) on cisplatin-induced nausea and vomiting, and the possible underlying mechanism. Kaolin intake was calculated daily in cisplatin-treated and saline-treated rats. Gastric motility recording, injections into the ARC, and lesions of the paraventricular nucleus (PVN) were used to study the effects of orexin-A and the hypothalamic nucleus on disorders of gastrointestinal function in cisplatin-treated rats. The pathway from the ARC to the PVN was observed through Fluoro-Gold retrograde tracing. Furthermore, an NPY Y1 receptor antagonist was administered to explore the possible mechanisms involved in the effects of orexin-A in the ARC. We illustrated that exogenous orexin-A injected into the ARC reduced kaolin intake and promoted gastric motility in cisplatin-treated rats, and these effects could have been blocked by an ipsilateral PVN lesion or co-injected antagonist of orexin-A-SB334867. Additional results showed that orexin-A-activated neurons in the ARC communicated directly with other neurons in the PVN that express neuropeptide Y (NPY). Furthermore, activation of the downstream NPY pathway was required for the observed effects of orexin in the ARC on cisplatin-induced nausea and vomiting. These findings reveal a novel neurobiological circuit from the ARC to the PVN that might provide a potential target for the prevention and treatment of cisplatin-induced nausea and vomiting.
Highlights
Cisplatin, as a chemotherapeutic agent, plays a core role in the multidrug chemotherapy of various malignancies, such as head and neck cancer, lung cancer and cervical cancer, etc. (Chen et al, 2017; Steuer et al, 2017; Szturz et al, 2018)
The results indicated that daily administration of orexin-A in the arcuate nucleus (ARC) effectively inhibited kaolin intake in cisplatin-treated rats
As the ARC is a sensor of metabolic signals, orexin receptor type 1 (OX1R)-containing neurons can be found throughout the nucleus (Guan et al, 2002)
Summary
As a chemotherapeutic agent, plays a core role in the multidrug chemotherapy of various malignancies, such as head and neck cancer, lung cancer and cervical cancer, etc. (Chen et al, 2017; Steuer et al, 2017; Szturz et al, 2018). (Chen et al, 2017; Steuer et al, 2017; Szturz et al, 2018) It is associated with a variety of side effects, such as nephrotoxicity, myelosuppression, and some gastrointestinal disorders like nausea, vomiting, and anorexia (Janicki, 2016). These symptoms adversely and severely affect the quality of life, reduce resistance to disease, and prevent completion of the course of chemotherapy. In cisplatin-treated rats, previous studies reported that most appetite-related peptides were modulated to exert anorexigenic effects, such as an increase in the levels of two key anorexigenic peptides, proopiomelanocortin (POMC) and the cocaine- and amphetamine-regulated transcript (CART), as well as the inhibition of the orexigenic peptides, neuropeptide Y and ghrelin (Liu et al, 2006; Yoshimura et al, 2013). Whether orexin, the peptide increased by cisplatin, affects food intake and nausea in cisplatin-treated rats remains unknown
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