Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 E. Second Street, Pomona, CA 91766, United States.
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 E. Second Street, Pomona, CA 91766, United States.
Eur J Pharmacol. 2018 Sep 5;834:157-168. doi: 10.1016/j.ejphar.2018.06.035. Epub 2018 Jun 30.
Ca plays a major role in maintaining cellular homeostasis and regulates processes including apoptotic cell death and side-effects of cancer chemotherapy including vomiting. Currently we explored the emetic mechanisms of FPL64176, an L-type Ca channel (LTCC) agonist with maximal emetogenic effect at its 10 mg/kg dose. FPL64176 evoked c-Fos immunoreactivity in shrew brainstem sections containing the vomit-associated nuclei, nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus. FPL64176 also increased phosphorylation of proteins ERK1/2, PKCα/βII and Akt in the brainstem. Moreover, their corresponding inhibitors (PD98059, GF 109203X and LY294002, respectively) reduced FPL64176-evoked vomiting. A 30 min subcutaneous (s.c.) pretreatment with the LTCC antagonist nifedipine (10 mg/kg) abolished FPL64176-elicited vomiting, c-Fos expression, and emetic effector phosphorylation. Ryanodine receptors (RyRs) and inositol trisphosphate receptors (IPRs) mediate intracellular Ca release from the sarcoplasmic/endoplasmic reticulum. The RyR antagonist dantrolene (i.p.), or a combination of low doses of nifedipine and dantrolene, but not the IPR antagonist 2-APB, significantly attenuated FPL64176-induced vomiting. The serotonin type 3 receptor (5-HTR) antagonist palonosetron (s.c.), the neurokinin 1 receptor (NKR) antagonist netupitant (i.p.) or a combination of non-effective doses of netupitant and palonosetron showed antiemetic potential against FPL64176-evoked vomiting. Serotonin (5-HT) and substance P immunostaining revealed FPL64176-induced emesis was accompanied by an increase in 5-HT but not SP-immunoreactivity in the dorsomedial subdivision of the NTS. These findings demonstrate that Ca mobilization through LTCCs and RyRs, and subsequent emetic effector phosphorylation and 5-HT release play important roles in FPL64176-induced emesis which can be prevented by 5-HTR and NKR antagonists.
钙在维持细胞内稳态方面发挥着重要作用，调节包括细胞凋亡和癌症化疗副作用（如呕吐）等过程。目前我们探索了 FPL64176 的呕吐机制，这是一种 L 型钙通道（LTCC）激动剂，在其 10mg/kg 剂量时具有最大的致呕作用。FPL64176 在含有呕吐相关核、孤束核（NTS）和迷走神经背核的雪貂脑干切片中引起 c-Fos 免疫反应。FPL64176 还增加了脑干中 ERK1/2、PKCα/βII 和 Akt 蛋白的磷酸化。此外，它们相应的抑制剂（分别为 PD98059、GF 109203X 和 LY294002）减少了 FPL64176 引起的呕吐。LTCC 拮抗剂硝苯地平（10mg/kg）皮下预处理 30 分钟可消除 FPL64176 引起的呕吐、c-Fos 表达和致呕效应器的磷酸化。兰尼碱受体（RyRs）和三磷酸肌醇受体（IPRs）介导肌浆/内质网内的细胞内钙释放。RyR 拮抗剂丹曲林（腹腔内）或硝苯地平与丹曲林的低剂量组合而非 IPR 拮抗剂 2-APB 显著减轻了 FPL64176 引起的呕吐。5-羟色胺 3 受体（5-HTR）拮抗剂帕洛诺司琼（皮下）、神经激肽 1 受体（NKR）拮抗剂奈妥吡坦（腹腔内）或奈妥吡坦和帕洛诺司琼的非有效剂量组合对 FPL64176 引起的呕吐表现出止吐潜力。5-羟色胺（5-HT）和 P 物质免疫染色显示，FPL64176 诱导的呕吐伴随着 NTS 背内侧亚区 5-HT 免疫反应性增加，但不伴有 SP-免疫反应性增加。这些发现表明，通过 LTCC 和 RyRs 动员钙，以及随后的致呕效应器磷酸化和 5-HT 释放，在 FPL64176 诱导的呕吐中发挥重要作用，5-HTR 和 NKR 拮抗剂可预防这种呕吐。
