The active fragments of ghrelin cross the blood-brain barrier and enter the brain to produce antinociceptive effects after systemic administration.

G (1-5)-NH2, G (1-7)-NH2, and G (1-9) are the active fragments of ghrelin. The aim of this study was to investigate the antinociceptive effects, their ability to cross the blood-brain barrier, and the receptor mechanism(s) of these fragments using the tail withdrawal test in male Kunming mice. The antinociceptive effects of these fragments (2, 6, 20, and 60 nmol/mouse) were tested at 5, 10, 20, 30, 40, 50, and 60 min after intravenous (i.v.) injection. These fragments induced dose- and time-related antinociceptive effects relative to saline. Using the near infrared fluorescence imaging experiments, our results showed that these fragments could cross the brain-blood barrier and enter the brain. The antinociceptive effects of these fragments were completely antagonized by naloxone (intracerebroventricular, i.c.v.); however, naloxone methiodide (intraperitoneal, i.p.), which is the peripheral restricted opioid receptor antagonist, did not antagonize these antinociceptive effects. Furthermore, the GHS-R1α antagonist [D-Lys3]-GHRP-6 (i.c.v.) completely antagonized these antinociceptive effects, too. These results suggested that these fragments induced antinociceptive effects through central opioid receptors and GHS-R1α. In conclusion, our studies indicated that these active fragments of ghrelin could cross the brain-blood barrier and enter the brain and induce antinociceptive effects through central opioid receptors and GHS-R1α after intravenous injection.

Application of high-speed counter-current chromatography combined with macroporous resin for rapid enrichment and separation of three anthraquinone glycosides and one stilbene glycoside from Rheum tanguticum.

In this paper, an efficient method was successfully established by the combination of macroporous resin (MR) and high-speed counter-current chromatography (HSCCC) for rapid enrichment and separation of aloe-emodin 8-O-ß-D-glucoside, emodin 1-O-ß-D-glucoside, emodin 8-O-ß-D-glucoside and piceatannol 4'-O-ß-D-(6″-O-gallate)-glucoside. Six kinds of macroporous resins were investigated in the first step and X-5 macroporous resin was selected for the enrichment of the target compounds. The recoveries of the target compounds reached 89.0, 85.9, 82.3 and 84.9% respectively after 40% ethanol elution. In the second step, the target compounds were separated by HSCCC with a two-phase solvent system composed of chloroform/ethyl acetate/methanol/water (8:1:6:5, v/v). The established method will be helpful for further characterization and utilization of Rheum tanguticum. The results demonstrate that MR coupled with HSCCC is a powerful technique for separation of bioactive compounds from natural products.

Differential effects of dexamethasone, ondansetron and a tachykinin NK1 receptor antagonist (GR205171) on cisplatin-induced changes in behaviour, food intake, pica and gastric function in rats.

This study aimed to dissect the mechanisms involved in malaise induced by the anti-cancer drug cisplatin by attempting to uncouple its effects on locomotor activity, arguably at least partly indicative of fatigue, from those effects indicative of emesis (pica, gastric stasis, reduced food intake) using pharmacological agents in the rat. Over 2 days cisplatin (6 mg/kg i.p.) reduced food intake, stimulated kaolin consumption, increased the wet weight of gastric contents and reduced locomotor activity. In animals treated with cisplatin: the 5-HT3 receptor antagonist ondansetron (1 mg/kg s.c. bd.) had no effect on either activity or weight of gastric contents but did increase food intake on day 1 (P<0.05) and the total over both days (27.6+/-1.8 vs. 19.9+/-2.3g, P<0.05), reducing kaolin consumption on day 2 (P<0.01) but not the total over both days; the NK1 receptor antagonist GR205171 (1 mg/kg s.c. bd.) was without effect on activity, but reduced the wet weight of gastric contents (P<0.05), increased food intake on day 2 (P<0.01) and total consumption over both days (28.1+/-1.7 g vs. 19.9+/-2.3 g; P<0.05) and reduced kaolin consumption on day 2 (P<0.05) but not over both days; dexamethasone (2 mg/kg s.c. bd.) blocked the cisplatin-induced reduction in activity on days 1 and 2 (P<0.01), reduced the wet weight of gastric contents by 43% (P<0.01), reduced kaolin consumption on both days (P<0.01) and arguably decreased the reduction in food intake caused by cisplatin. This study has revealed novel insights into the different spectra of activities of 5-HT3 and NK1 receptor antagonists and dexamethasone, which have implications for therapeutic strategies to alleviate the emetic, anorectic, dyspeptic and activity-reducing effects of anti-cancer chemotherapy.

Pica--a model of nausea? Species differences in response to cisplatin.

Rats lack the emetic reflex but exhibit pica in response to stimuli that induce emesis in species with an emetic reflex, hence it has been proposed that pica may be analogous to emesis in species lacking the reflex. In the present study, we investigated whether pica was present in Suncus murinus (with an emetic reflex) as well as in rats and mice (without emetic reflex) to provide a further insight to the validity of pica as a model for nausea/vomiting. Cisplatin (6 mg/kg, i.p.) induced pica in rats, indicated by a significant increase in kaolin consumption at 24 h (but not 48 h) post-treatment whereas we failed to demonstrate this effect in mice (inbred or outbred strain, 6 or 20 mg/kg i.p.) and whilst cisplatin (20 mg/kg, i.p.) induced emesis in Suncus, kaolin intake was not significantly affected. Furthermore, cisplatin significantly increased the weight of gastric contents at 48 h post-injection in rats and mice indicating delayed gastric emptying whereas this effect was not present in Suncus. These results show that Suncus and two strains of mice, unlike rats, do not develop pica in response to cisplatin which suggests that the consumption of kaolin induced by cisplatin may not be associated with whether or not an emetic reflex is present. The differences in ingestive behaviour and gastric response between species with and without an emetic reflex in response to cisplatin treatment as well as the difference between mice and rats, is discussed in relation to the selection of models for the study of nausea and vomiting.

Potential energetic implications of emesis in the house musk shrew (Suncus murinus).

During the course of studies investigating novel anti-emetic therapies we serendipitously observed a previously unreported behaviour related to emesis in the house musk shrew. This behaviour consisted of spontaneous ingestion of vomit in about half of the animals (males and females) in which emesis was induced by either nicotine (4 mg kg-1 sc.) or horizontal motion (1 Hz, 4 cm, 10 min). Analysis of vomit samples and gastric contents revealed that in a "typical" individual the gastric contents would be voided by as few as 3 vomits. Energetic calculations of the metabolisable energy of food, gastric contents, vomit and field metabolic rate (FMR) predict that a male weighing 60 g would lose 17.3% of its hourly energy requirement for FMR if it vomited once. A 40 g female, however, would experience an hourly energy loss of approximately 22.8%. The possible energetic consequences and resulting ecological implications of this unusual behaviour are discussed.

Pharmacological characterisation of the thermogenic effect of bupropion.

The pharmacological mechanism of bupropion's thermogenic effect has been investigated in female Wistar rats by measuring oxygen consumption at thermoneutrality (29 degrees C). Bupropion (30 mg/kg) rapidly increased oxygen consumption (VO2) with a maximum effect at 30 min, and VO2 remained elevated throughout the 4-h experimental period. The nonselective 5-hydroxytryptamine (5-HT or serotonin) receptor antagonist, metergoline (1 mg/kg), and the alpha1-adrenoceptor antagonist, prazosin (1 mg/kg), had no effect on the VO2 response to bupropion, whereas the alpha2-adrenoceptor antagonist, RS79948 [(8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine hydrochloride] (1 mg/kg), potentiated the response. The VO2 response to bupropion during the first 60 min was significantly inhibited by a high dose of the nonselective beta-adrenoceptor antagonist, propranolol (20 mg/kg), but it had no effect at a low dose (1 mg/kg). Pretreatment with the dopamine D2/D1 receptor antagonist, (+)butaclamol (200 microg/kg), caused a partial, but significant, inhibition (P<0.01) of the VO2 response to bupropion during the first 60 min, and this antagonist abolished the effect of bupropion between 90 and 240 min. Pretreatment with a combination of a high dose of propranolol (20 mg/kg) and (+)butaclamol (200 microg/kg) prevented any increase in VO2 induced by bupropion. It is concluded that the beta3-adrenoceptor subtype, as well as dopamine D2/D1 receptors, is responsible for the increase in oxygen consumption induced by bupropion. We have previously demonstrated that bupropion did not significantly reduce food intake in rats. Hence, in this species, its weight-reducing action predominantly results from thermogenesis mediated via activation of beta3-adrenergic and dopamine D2/D1 receptors. Because bupropion has also been reported not to alter food intake in the clinic, thermogenesis may also contribute to its antiobesity effect in man.

Anorectic actions of prolactin-releasing peptide are mediated by corticotropin-releasing hormone receptors.

Prolactin-releasing peptide (PrRP) reduces food intake and body weight and modifies body temperature when administered centrally in rats, suggesting a role in energy homeostasis. However, the mediators of PrRP's actions are unknown. The present study, therefore, first examined the possible involvement of the anorectic neuropeptides corticotropin-releasing hormone (CRH) and the melanocortins (e.g., alpha-melanocyte-stimulating hormone) in PrRP's effects on food intake and core body temperature and, second, determined if PrRP affects energy expenditure by measuring oxygen consumption (Vo2). Intracerebroventricular injection of PrRP (4 nmol) to 24-h-fasted male Sprague-Dawley rats decreased food intake and modified body temperature. Blockade of central CRH receptors by intracerebroventricular coadministration of the CRH receptor antagonist astressin (20 microg) reversed the PrRP-induced reduction in feeding. However, astressin's effect on PrRP-induced changes in body temperature was complicated because the antagonist itself caused a slight rise in body temperature. In contrast, intracerebroventricular coadministration of the melanocortin receptor-3/4 antagonist SHU-9119 (0.1 nmol) had no effect on any of PrRP's actions. Finally, intracerebroventricular injection of PrRP (4 nmol) caused a significantly greater Vo2 over a 3-h test period compared with vehicle-treated rats. These results show that the anorectic actions of PrRP are mediated by central CRH receptors but not by melanocortin receptors-3/4 and that PrRP can modify Vo2.

Comparison of the thermogenic and hypophagic effects of sibutramine's metabolite 2 and other monoamine reuptake inhibitors.

The thermogenic and hypophagic effects of sibutramine's metabolite (metabolite 2), a 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor, were investigated in rats and compared with duloxetine and bupropion. Metabolite 2 increased colonic temperature for 2.5-4.5 h. Duloxetine was also thermogenic but was less effective than metabolite 2. Bupropion similarly increased colonic temperature and was as efficacious, but less potent, than metabolite 2. At -8 degrees C, metabolite 2, duloxetine and bupropion all decreased response to heat reinforcement and reduced colonic temperature. Metabolite 2 produced a sustained increase in oxygen consumption (VO(2)) at 29 degrees C from 90 to 240 min, whereas duloxetine was far less effective. Bupropion rapidly enhanced VO(2), but its effect was less prolonged than that of metabolite 2. Metabolite 2 markedly reduced 24-h food intake. Duloxetine decreased feeding although its effect was shorter-lived, but bupropion was without effect. Thus, sibutramine's antiobesity action is probably attributable to effects on energy intake and expenditure. Duloxetine shares these properties, but is generally less efficacious. Any potential weight-reducing effect of bupropion is probably due to thermogenesis.