[PubMed] [Google Scholar]. some of the discussed questions in current emesis-related literature. This was accomplished by: 1) investigating whether peripheral administration of SP, or of brain penetrating and non-penetrating NK1 receptor agonists, can induce emesis and scratching dose-dependently; 2) pharmacologically deciphering which tachykinin receptor is responsible for the induction of these behaviors via the utilization of selective receptor agonists and antagonists; 3) determining whether intraperitoneally-administered SP at emetic doses can enter the brain by analyzing the tissue levels of exogenous SP in the brain stem and frontal cortex; 4) examining Fos-measured neuronal activity in the DVC and GIT enteric neurons following systemic administration of GR73632; and 5) demonstrating the possible role of peripheral NK1 receptors in emesis following their selective peripheral ablation in the PIK-90 gut. 2. RESULTS Dose-response emesis and scratching studies with tachykinin receptor agonists and antagonists Intraperitoneal administration of SP (0, 10, 25, 50 and 100 mg/kg) increased the frequency of vomiting [(KW (4, 40) = 25.7, P 0.0001)] (Fig 1A). Dunns multiple comparisons posthoc test showed that relative to the vehicle-treated control group, significant increases PIK-90 in the frequency of vomiting occurred in groups injected PIK-90 with the 50 (382%, P 0. 01) and 100 (322%, P 0.05) mg/kg doses of SP. The 10 and 25 mg/kg doses of SP were inactive. The onset of first emesis was rapid, within 1C2 min of SP injection, and the majority of episodes occurred within the first 5 minutes, except one animal which vomited at 25 minutes. Fishers exact test showed that the percentage of shrews vomiting in response to SP administration increased in a dose-dependent manner [(2 (4, 40) = 27.7, P 0.0001)] (Fig. 1B). Significant increases (82 and 78%, respectively) in the number of shrews vomiting were seen at 50 (P 0.001) and 100 mg/kg (P 0.001) doses of SP. Although in our initial dose-response studies not all shrews vomited in response to either 50 or 100 mg/kg doses of SP, in our subsequent drug interaction studies, all vehicle-pretreated animals vomited in response to 50 mg/kg SP injection. At the doses tested, SP caused no other FLJ31945 overt behavioral effect (e.g. PIK-90 scratching). Open in a separate window Figure 1 The dose-response emetic effects of varying doses of intraperitoneally-administered substance P (Graphs A and B) and the brain penetrating NK1 receptor selective agonist GR73632 (graphs C and D), during the 30 min post-injection observation period in the least shrew. Graphs A and C depict increases in the frequency of emesis (mean S.E.M.), whereas graphs B and D show the percentage of shrews vomiting. Significantly different from corresponding vehicle control (0 mg/kg) at P 0.05 (*), P 0.01 (**) and P 0.001 (***). The brain penetrating and selective NK1 receptor agonist GR73632 (0, 1, 2.5 and 5 mg/kg) increased the frequency of vomiting in a dose-dependent manner [(KW (3, 32) = 24.9, P 0.0002)] (Fig 1C). Significant increases in emesis frequency occurred at 2.5 (438%, P 0.01) and 5 mg/kg (575%, P 0.001) doses. The percentage of shrews vomiting also increased in a dose-dependent fashion [(2 (3, 32) = 26.5, P 0.0001)] and significant increases in the number of shrews vomiting were observed at 2.5 (87.5%, P 0.001) and 5 mg/kg (100%, P 0.001) doses (Fig. 1D). The onset of first emesis was rapid and generally occurred within 3C4 minutes of GR73632 administration and the remaining episodes occurred in the next 15 minutes. Although SP failed to cause scratchings, intraperitoneal injection of GR73632 also caused dose-dependent increases in the frequency of scratching behavior (KW [(3, 30) = 24, P 0.0001)] (Fig. 2A). Significant increases were seen at 2.5 (P 0.001) and 5 mg/kg doses (P 0.001) (Fig. 2A). The PIK-90 CNS non-penetrating NK1 receptor agonists produced minimal emetic and scratching behaviors which were not significantly different from their corresponding vehicle-treated controls. Thus, ASMSP caused emesis in 37% (3 of 8 shrews vomiting), 50% (4 of 8), and 50%.
