The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva).

摘要: Subtypes (1-4) of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in central and peripheral nervous systems, as well cells smooth muscles many organs. They mainly serve to regulate cellular excitability these tissues. The HCN channel blocker ZD7288 has been shown reduce apomorphine-induced conditioned taste aversion on saccharin preference rats suggesting potential antinausea/antiemetic effects. Currently, least shew model emesis we find that induces vomiting a dose-dependent manner, with maximal efficacies 100% at 1 mg/kg (i.p.) 83.3% 10 µg (i.c.v.). subtype expression was assessed using immunohistochemistry shrew brainstem dorsal vagal complex (DVC) containing emetic nuclei (area postrema (AP), nucleus tractus solitarius motor vagus). Highly enriched HCN1 HCN4 subtypes present AP. A dose strongly evoked c-Fos ERK1/2 phosphorylation DVC, but not enteric system jejunum, contribution vomiting. ZD7288-evoked exclusively occurred tryptophan hydroxylase 2-positive serotonin neurons complex, indicating activation may contribute ZD7288-induced To reveal its mechanism(s) action, evaluated efficacy diverse antiemetics against including antagonists/inhibitors of: (U0126), L-type Ca2+ (nifedipine); store-operated entry (MRS 1845); T-type (Z944), IP3R (2-APB), RyR receptor (dantrolene); serotoninergic type 3 (palonosetron); neurokinin (netupitant), dopamine 2 (sulpride), transient vanilloid agonist, resiniferatoxin. All tested except sulpride attenuated varying degrees. In sum, via mechanisms, process which involves signaling several receptors. blockers have reported clinic since they currently used/investigated therapeutic candidates for cancer therapy related- or unrelated-heart failure, pain, cognitive impairment.