Ghrelin's excitatory effect on gastric neurons is significantly blunted by cisplatin chemotherapy in rats
Background
Cisplatin is a powerful and widely used antineoplastic drug for treating various cancers. However, its clinical utility is often limited by severe side effects, including debilitating nausea, vomiting, and dyspepsia. The precise neurological mechanisms driving these gastrointestinal issues are not fully understood, complicating their management. The dorsal vagal complex (DVC) is a key brainstem area integrating signals from the gut, and ghrelin, a gut-brain hormone, is known to modulate appetite and gastric function. This study investigates how cisplatin treatment alters the response of gastric distention-sensitive neurons within the DVC to both ghrelin and stimulation from the lateral hypothalamus area (LHA), a brain region involved in hunger signaling.
Study Design
The study used both cisplatin-treated and saline-treated (control) rats. Researchers performed extracellular discharge recording to measure the firing frequency of gastric distention (GD) sensitive neurons in the dorsal vagal complex (DVC). They microinjected ghrelin directly into the DVC to observe its effects. In separate experiments, they pre-treated the DVC with the ghrelin receptor antagonist [D-Lys-3]-GHRP-6 before ghrelin administration to confirm receptor-specific action. They also used electrical stimulation of the lateral hypothalamus area (LHA) to assess its influence on these same DVC neurons.
Results
Two types of neurons were identified in the DVC: gastric distention-excitatory (GD-E) and gastric distention-inhibitory (GD-I). In control rats, microinjection of ghrelin into the DVC increased the firing frequency of most GD neurons. However, this excitatory effect was significantly blunted in cisplatin-treated rats. The ghrelin receptor antagonist, [D-Lys-3]-GHRP-6, completely eliminated the excitatory effects of ghrelin, confirming the action was mediated through the ghrelin receptor. Similarly, electrical stimulation of the lateral hypothalamus area (LHA) increased the firing frequency of DVC neurons.
This excitatory effect from LHA stimulation was also weaker in cisplatin-treated rats compared to saline-treated rats. Crucially, pretreatment with
[D-Lys-3]-GHRP-6only partly blocked the excitatory effect of LHA stimulation, suggesting that LHA signaling to the DVC is only partially mediated by ghrelin.
Key Findings
- Microinjection of ghrelin into the DVC increased firing frequency of gastric distention (GD) neurons.
- The excitatory effect of ghrelin on GD neurons was significantly lower in cisplatin-treated rats versus saline-treated rats.
- Ghrelin receptor antagonist [D-Lys-3]-GHRP-6 completely eliminated the excitatory effect of ghrelin.
- Electrical stimulation of the LHA also excited GD neurons, but this effect was weaker in cisplatin-treated rats.
- [D-Lys-3]-GHRP-6 only partly blocked the excitatory effects of LHA stimulation on DVC neurons.
Why It Matters
This research provides a potential neurological explanation for the severe dyspepsia and appetite loss caused by cisplatin chemotherapy. It suggests that cisplatin treatment dampens the normal signaling response of key gastric neurons to ghrelin, a primary hunger and gastric motility hormone. For individuals using peptides, this implies that the efficacy of ghrelin mimetics (like GHRP-6, Ipamorelin, etc.) for stimulating appetite might be significantly reduced during active cisplatin therapy. Targeting the ghrelin receptor system might offer a therapeutic avenue to alleviate chemotherapy-induced gastric side effects, but simply administering ghrelin agonists may not be sufficient due to this observed neuronal desensitization. The study highlights a specific mechanism of cisplatin's side effects, paving the way for more targeted interventions beyond standard antiemetics.
