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.