2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Vomiting

We previously reported that intra-4th-ventricular (i.4th.v.) administration of a non-NMDA receptor antagonist, NBQX, abolished vagally induced retching. This study was undertaken to ascertain whether or not the neuronal response in the solitary tract nucleus (NTS) to vagal stimulation and the vago-vagal gastric reflexes induced by non-emetic stimulation are also abolished by NBQX with a similar latency as in the case of retching. Ketamine and thiopental- or chloralose-anesthetized dogs were decerebrated, and the dorsal surface of the medulla was exposed. This study consisted of two series of experiments. In the first series, extracellular neuronal responses in the NTS to pulse-train vagal stimulation were recorded. Effects of NBQX on the neural response and vagally induced fictive retching were observed. In the second series, effects of glutamate receptor antagonists on gastric corpus responses to esophageal or gastric antral distension were observed. Retching was abolished 5-15 min after an i.4th.v. application of NBQX. and the neuronal responses disappeared within 14 min after application in nine of 10 NTS neurons. On the other hand, corpus contractility was inhibited by esophageal distension, and inhibited and/or enhanced by antral distension. While the inhibitory responses disappeared within 17 min after NBQX, the enhanced response remained even after NBQX and vagotomy, but was abolished by i.v. administration of hexamethonium. These results suggest that adaptive relaxation in the corpus, as well as retching, may be mediated by glutaminergic vagal afferents and non-NMDA receptors in the NTS.

Topics: Action Potentials; Animals; Catheterization; Dizocilpine Maleate; Dogs; Esophagus; Excitatory Amino Acid Antagonists; Ganglionic Blockers; Glutamic Acid; Hexamethonium; Neurons, Afferent; Quinoxalines; Reflex; Solitary Nucleus; Stomach; Vagotomy; Vagus Nerve; Vomiting

The effects of the N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists MK-801 and NBQX, respectively, on salivary secretion and retching induced by vagal stimulation were studied in decerebrate dogs. Vagal stimulation induced an increase in salivary secretion and fictive retching. Intra-4th ventricular application of vehicle or MK-801 did not change either response, while NBQX completely abolished both responses. These results suggest that non-NMDA receptors mediate both responses in the solitary nucleus.

Topics: Anesthesia; Animals; Decerebrate State; Dizocilpine Maleate; Dogs; Electric Stimulation; Excitatory Amino Acid Antagonists; Lingual Nerve; Phrenic Nerve; Quinoxalines; Reaction Time; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Salivation; Solitary Nucleus; Synaptic Transmission; Vagus Nerve; Vomiting

The excitatory amino acid (EAA) receptor antagonists, 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo(f)quinoxaline (NBQX) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), which preferentially block non-N-methyl-D-aspartate (non-NMDA) subtypes of EAA receptors, effectively inhibit cisplatin-induced emesis in ferrets. A high dose of cisplatin (10 mg/kg i.v.) was used which induced emesis in all saline-treated control ferrets. At 10 mg/kg i.v., NBQX totally prevented cisplatin-induced emesis in 5 of 6 ferrets and CNQX totally prevented emesis in 3 of 5 ferrets. By comparison, each of the 5-HT3 inhibitors, zacopride and ondansetron, at 1.0 mg/kg i.v. (a dose considered in the high therapeutic range for controlling emesis by these compounds), totally prevented emesis in 2 of 5 ferrets. It is concluded that non-NMDA antagonists effectively inhibit cisplatin-induced emesis. They are potential antiemetic compounds, alone or in combination with 5-HT3 antagonists or other more conventional drugs of choice.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cisplatin; Exploratory Behavior; Ferrets; Imidazoles; Male; Ondansetron; Quinoxalines; Receptors, Amino Acid; Receptors, Cell Surface; Serotonin Antagonists; Vomiting