Ghrelin stimulates gastric motility of the guinea pig through activation of a capsaicin‐sensitive neural pathway: in vivo and in vitro functional studies

Background Ghrelin stimulates gastric motility in rats, mice and humans. Although ghrelin and the ghrelin receptor are known to be expressed in the guinea‐pig gastrointestinal tract, the effects of ghrelin on gastric motility have not been examined. Aim of the present study was to clarify the motor‐stimulating action of ghrelin in the guinea‐pig stomach. Methods Gastric motility was measured as intraluminal pressure changes using a balloon inserted in the stomach of urethane‐anaesthetized guinea pigs. The effects of ghrelin on gastric muscle contraction and [³H]‐efflux from [³H]‐choline‐loaded strips were investigated in vitro. Key Results Ghrelin (0.3–30 μg kg^?1, i.v.) increased gastric motility in a dose‐dependent manner but des‐acyl ghrelin was ineffective. The action of ghrelin was completely inhibited by hexamethonium and d ‐Lys³‐growth‐hormone releasing peptide‐6. Atropine partially decreased the stimulatory action of ghrelin. In capsaicin‐pretreated guinea pigs, the ghrelin‐induced response was markedly decreased. Ghrelin (1 μmol L^?1) did not affect [³H]‐efflux in non‐stimulated preparations but significantly decreased electrical field stimulation (EFS)‐induced [³H]‐efflux. l ‐Nitro arginine methylester (l ‐NAME) attenuated the inhibition of [³H]‐efflux by ghrelin. Ghrelin did not cause any mechanical changes in gastric strips. Electrical field stimulation caused relaxation of gastric strips, which changed to atropine‐sensitive contraction in the presence of l ‐NAME. Relaxation induced by EFS was slightly potentiated, but the EFS‐induced contraction was not affected by ghrelin. Conclusions & Inferences Ghrelin stimulates gastric motility of the guinea pig through activation of capsaicin‐sensitive vago‐vagal reflex pathway including efferent cholinergic neurons. Peripheral ghrelin receptors on enteric nitrergic nerves might affect the ghrelin‐induced gastric action by releasing nitric oxide.     

Actions of prolonged ghrelin infusion on gastrointestinal transit and glucose homeostasis in humans

Background Ghrelin is produced by enteroendocrine cells in the gastric mucosa and stimulates gastric emptying in healthy volunteers and patients with gastroparesis in short‐term studies. The aim of this study was to evaluate effects of intravenous ghrelin on gastrointestinal motility and glucose homeostasis during a 6‐h infusion in humans. Methods Ghrelin (15 pmol kg^?1 min^?1) or saline was infused intravenously for 360 min after intake of radio‐opaque markers, acetaminophen, and lactulose after a standardized breakfast in 12 male volunteers. Gastric emptying, orocecal transit, colonic transit, postprandial plasma concentrations of glucose, insulin, glucagon‐like peptide‐1 (GLP‐1), and peptide YY were assessed. In vitro studies of gastrointestinal muscle contractility were performed. Key Results The gastric emptying rate was faster for ghrelin compared to saline (P = 0.002) with a shorter half‐emptying time (50.3 ± 3.9 vs 59.9 ± 4.4 min, P = 0.004). There was no effect of ghrelin on orocecal or colonic transit. Postprandial elevations of plasma glucose, insulin, and GLP‐1 occurred 15 min earlier and were higher with ghrelin. The insulinogenic index did not change during ghrelin infusion. Basal in vitro contractility was unaffected by ghrelin. Conclusions & Inferences The effect of a 6‐h ghrelin infusion on gastrointestinal motility is limited to the stomach without affecting orocecal or colonic transit. Plasma glucose, insulin, and GLP‐1 are elevated postprandially, probably as a result of the hastened gastric emptying. Changes in glucose homeostasis as a consequence of stimulated gastric emptying and hormone release, need to be taken into account in the use of pharmacological stimulants for the treatment of motility disorders.     

Comparative evaluation of DQ-2511, a novel gastroprokinetic agent,with cisapride in ameliorative action on experimentally induced delayed gastric emptying

We compared the main pharmacological effect of DQ-2511 (3-[[[2-(3,4-dimethoxyphenyl)-ethyl]carbamoyl]methyl]amino -N- methylbenzamide), a novel gastroprokinetic agent, with that of cisapride. Single oral administration of DQ-2511 (3–10 mg kg^?1) caused similar significant improvements to delays in gastric emptying of semi-solid meals evoked by chole-cystokinin-octapeptide (CCK₈: 5 μ kg^?1, i.v.) in monkeys, to that with cisapride (3 mg kg^?1). A 2-week oral treatment of unilaterally vagotomized rats with DQ-2511 (1–10 mg kg^?1) lessened delays in gastric emptying, whereas cisapride (0.3–10 mg kg^?1) had no effect under the same experimental protocols. In anesthetized rats, bolus intravenous injection of either compound (60 μg kg^?1) enhanced gastric motility determined by means of strain gauge force transducers. Electrophysiological investigations revealed that bolus injection of DQ-2511 (6–60 μ kg^?1) depressed the afferent discharge rate of the ventral gastric branch of the vagus nerve, while cisapride showed no effect. These results suggest that the mechanism of ameliorative action of DQ-2511 on delayed gastric emptying may differ from that of cisapride.     

Gastric secretion but not nitric oxide is involved in pentagastrin-induced gastric relaxation in conscious dogs

Gastrin delays gastric emptying of liquids probably by reducing gastric tone. The mechanism responsible for the relaxatory effect induced by pentagastrin was unknown. The aim of this study was to investigate the effects of pentagastrin and the underlying mechanisms responsible for these effects. Could nitric oxide (NO) be involved as a mediator? Gastric tone was monitored with a flaccid bag introduced into the stomach via a gastric cannula and connected to a barostat. A series of pressure–volume curves with a 30-min interval were constructed by increasing intragastric pressure to a maximum of 14 mmHg (2-mmHg steps). Pentagastrin (4 μg kg^?1 s.c.) facilitated the volume increases induced by isobaric gastric distension. This effect could be completely blocked by pretreatment with cimetidine (10 mg kg^?1 s.c.) or by omeprazole (10 mg kg^?1 p.o.). The effect induced by pentagastrin could be mimicked by histamine (0.16 mg kg^?1 s.c.) and to a lesser extent by insulin (0.2 IU kg^?1 i.v.). Cimetidine and omeprazole had no intrinsic effect on gastric tone. With an opened cannula, allowing the gastric secretions to leave the stomach, no increased gastric relaxation could be observed either in the presence of pentagastrin or in the presence of histamine or insulin. Nitro-l-arginine (L-NNA, 5 mg kg^?1 i.v.) reduced the volume increases induced by distension. Unexpectedly, even in the presence of L-NNA, pentagastrin remained effective. In conclusion, pentagastrin induces a gastric relaxation via a mechanism which involves gastric secretion but not nitric oxide.     

Central administration of pan‐somatostatin agonist ODT8‐SST prevents abdominal surgery‐induced inhibition of circulating ghrelin,food intake and gastric emptying in rats

Background Activation of brain somatostatin receptors (sst_1–5) with the stable pan‐sst_1–5 somatostatin agonist, ODT8‐SST blocks acute stress and central corticotropin‐releasing factor (CRF)‐mediated activation of endocrine and adrenal sympathetic responses. Brain CRF signaling is involved in delaying gastric emptying (GE) immediately post surgery. We investigated whether activation of brain sst signaling pathways modulates surgical stress‐induced inhibition of gastric emptying and food intake. Methods Fasted rats were injected intracisternally (i.c.) with somatostatin agonists and underwent laparotomy and 1‐min cecal palpation. Gastric emptying of a non‐nutrient solution and circulating acyl and desacyl ghrelin levels were assessed 50 min post surgery. Food intake was monitored for 24 h. Key Results The abdominal surgery‐induced inhibition of GE (65%), food intake (73% at 2 h) and plasma acyl ghrelin levels (67%) was completely prevented by ODT8‐SST (1 μg per rat, i.c.). The selective sst₅ agonist, BIM‐23052 prevented surgery‐induced delayed GE, whereas selective sst₁, sst₂, or sst₄ agonists had no effect. However, the selective sst₂ agonist, S‐346‐011 (1 μg per rat, i.c.) counteracted the abdominal surgery‐induced inhibition of acyl ghrelin and food intake but not the delayed GE. The ghrelin receptor antagonist, [D‐Lys³]‐GHRP‐6 (0.93 mg kg^?1, intraperitoneal, i.p.) blocked i.p. ghrelin‐induced increased GE, while not influencing i.c. ODT8‐SST‐induced prevention of delayed GE and reduced food intake after surgery. Conclusions & Inferences ODT8‐SST acts in the brain to prevent surgery‐induced delayed GE likely via activating sst₅. ODT8‐SST and the sst₂ agonist prevent the abdominal surgery‐induced decrease in food intake and plasma acyl ghrelin indicating dissociation between brain somatostatin signaling involved in preventing surgery‐induced suppression of GE and feeding response.     

Endogenous and exogenous ghrelin enhance the colonic and gastric manifestations of dextran sodium sulphate-induced colitis in mice

Abstract Ghrelin is an important orexigenic peptide that not only exerts gastroprokinetic but also immunoregulatory effects. This study aimed to assess the role of endogenous and exogenous ghrelin in the pathogenesis of colitis and in the disturbances of gastric emptying and colonic contractility during this process. Dextran sodium sulphate colitis was induced for 5 days in (i) ghrelin^+/+ and ghrelin^?/? mice and clinical and histological parameters were monitored at days 5, 10 and 26 and (ii) in Naval Medical Research Institute non‐inbred Swiss (NMRI) mice treated with ghrelin (100 nmol kg^?1) twice daily for 5 or 10 days. Neural contractility changes were measured in colonic smooth muscle strips, whereas gastric emptying was measured with the ¹⁴C octanoic acid breath test. Inflammation increased ghrelin plasma levels. Body weight loss, histological damage, myeloperoxidase activity and IL‐1β levels were attenuated in ghrelin^?/? mice. Whereas absence of ghrelin did not affect changes in colonic contractility, gastric emptying in the acute phase was accelerated in ghrelin^+/+ but not in ghrelin^?/? mice. In agreement with the studies in ghrelin knockout mice, 10 days treatment of NMRI mice with exogenous ghrelin enhanced the clinical disease activity and promoted infiltration of neutrophils and colonic IL‐1β levels. Unexpectedly, ghrelin treatment decreased excitatory and inhibitory neural responses in the colon of healthy but not of inflamed NMRI mice. Endogenous ghrelin enhances the course of the inflammatory process and is involved in the disturbances of gastric emptying associated with colitis. Treatment with exogenous ghrelin aggravates colitis, thereby limiting the potential therapeutic properties of ghrelin during intestinal inflammation.     

The nitric oxide synthase inhibitor, Ng-nitro-l-arginine-methyl-ester, attenuates the delay in gastric emptying induced by hyperglycaemia in healthy humans

Abstract The aim of this study was to determine whether the nitric oxide (NO) synthase inhibitor, N^g‐nitro‐l ‐arginine‐methyl‐ester (l ‐NAME), reverses the effects of acute hyperglycaemia on gastric emptying and antropyloroduodenal (APD) motility. The study had a four‐way randomized crossover (hyperglycaemia vs euglycaemia; l ‐NAME vs placebo) design in a clinical laboratory setting. Seven healthy volunteers [four males; age 30.3 ± 3.8 years; body mass index (BMI) 23.6 ± 1.2 kg m^?2] were the study subjects. After positioning a transnasal manometry catheter across the pylorus, the blood glucose concentration was maintained at either 15 or 5 mmol L^?1 using a glucose/insulin clamp. An intravenous infusion of l ‐NAME (180 μg kg^?1 h^?1) or placebo (0.9% saline) was commenced (T = ?30 min) and continued for 150 min. At T = ?2 min, subjects ingested a drink containing 50 g of glucose made up to 300 mL with water. Gastric emptying was measured using 3D ultrasound, and APD motility using manometry. Hyperglycaemia slowed gastric emptying (P < 0.05), and this effect was abolished by l ‐NAME. l ‐NAME had no effect on gastric emptying during euglycaemia. Hyperglycaemia suppressed fasting antral motility [motility index: 3.9 ± 0.8 (hyperglycaemia) vs 6.5 ± 0.6 (euglycaemia); P < 0.01]; l ‐NAME suppressed postprandial antral motility [motility index: 3.6 ± 0.2 (l ‐NAME) vs 5.1 ± 0.2 (placebo); P < 0.001]. Postprandial basal pyloric pressure was higher during hyperglycaemia (P < 0.001), and lower after administration of l ‐NAME (P < 0.001). Slowing of gastric emptying induced by hyperglycaemia is mediated by NO, and may involve the modulation of tonic pyloric activity.     

Influence of gastric acid on gastric emptying and gastric distension-induced pain response in rats - effects of famotidine and mosapride

Background Gastroduodenal acidification has been reported to aggravate upper abdominal discomfort and pain that are symptoms suffered by functional dyspepsia (FD) patients. Delayed gastric emptying and hypersensitivity to gastric distension (GD) contribute importantly to the pathophysiology of FD. Methods In the present study, we determined the influence of pentagastrin‐stimulated endogenous gastric acid on gastric emptying and GD‐induced pain responses using rat model systems. Moreover, we evaluated the effects of famotidine and mosapride on changes in gastric emptying and the GD‐induced pain response to gastric acid hypersecretion. Gastric emptying was measured by excretion of glass beads that had been intragastrically administered with a liquid nutrient, and gastric pain response was evaluated by observing whether a GD‐induced increase in mean blood pressure occurred. Key Results Pentagastrin (2 mg kg^?1, s.c.) which markedly and continuously stimulated gastric acid secretion, significantly delayed and enhanced respectively, gastric emptying and pain compared with saline‐injected groups. Oral famotidine (0.1–3 mg kg^?1) and mosapride (0.3–3 mg kg^?1) administration in a dose‐dependent manner accelerated the delay of gastric emptying. Furthermore, famotidine (0.3–3 mg kg^?1) significantly alleviated the aggravation of the GD‐induced pain response, but mosapride (10 mg kg^?1) did not. Conclusions & Inferences We established rat models to evaluate the effect of gastric acid hypersecretion on gastric emptying and the GD‐induced pain response. In these models, acid hypersecretion delayed gastric emptying and aggravated the pain response. Furthermore, we showed that famotidine ameliorated both delayed gastric emptying and gastric hypersensitivity, whereas mosapride only improved delayed gastric emptying.     

Tissue ghrelin level and gastric emptying rate in adult patients with celiac disease

Abstract Celiac disease (CD) patients show a number of gastrointestinal motor abnormalities. Ghrelin, a gastric peptide implicated in short‐term feeding control and long‐term body weight regulation, has been recently considered a key regulator of gastric motility. The aim of this study was to evaluate the gastric emptying rate of solids and the density of ghrelin‐immunopositive cells in adult CD patients before and at least 1 year after starting a gluten‐free diet. Twenty CD patients (M 8/F 12; mean age 36 years) and 10 controls underwent endoscopy with gastric and duodenal biopsies and ¹³C‐octanoic acid breath test to measure gastric emptying of solids. Celiac disease patients repeated the protocol at least 1 year after starting gluten‐free diet. Ghrelin tissue levels were evaluated by immunohistochemistry on gastric mucosa specimens. Gastric emptying time was normal in all control subjects (t_1/2 = 89 ± 16 min) while it was delayed in CD patients prior to gluten‐free diet (t_1/2 = 252 ± 101 min; P < 0.005). The mean number of ghrelin‐positive cells/field (×400) was 14.4 ± 2.7 in controls and 25.3 ± 5.7 in CD patients respectively (P < 0.0001). Gluten withdrawal was effective in normalizing gastric emptying time in all CD patients (97 ± 14 min; P < 0.0001) and resulted in a significant reduction of the density of ghrelin‐immunopositive cells (19.8 ± 5.4; P < 0.0001). The density of ghrelin‐positive cells correlated directly with the degree of duodenal damage (P < 0.001) and inversely with the body mass index of CD patients (P < 0.0001). However, in neither CD patients nor controls, a correlation between tissue ghrelin levels and gastric emptying rate was detected. In conclusion, tissue ghrelin level does not correlate with gastric emptying rate in adult CD patients and in controls.     

Secretin-induced gastric relaxation is mediated by vasoactive intestinal polypeptide and prostaglandin pathways

Abstract Secretin has been shown to delay gastric emptying and inhibit gastric motility. We have demonstrated that secretin acts on the afferent vagal pathway to induce gastric relaxation in the rat. However, the efferent pathway that mediates the action of secretin on gastric motility remains unknown. We recorded the response of intragastric pressure to graded doses of secretin administered intravenously to anaesthetized rats using a balloon attached to a catheter and placed in the body of the stomach. Secretin evoked a dose‐dependent decrease in intragastric pressure. The threshold dose of secretin was 1.4 pmol kg^?1 h^?1 and the effective dose, 50% was 5.6 pmol kg^?1 h^?1. Pretreatment with hexamethonium markedly reduced gastric relaxation induced by secretin (5.6 pmol kg^?1 h^?1). Bilateral vagotomy also significantly reduced gastric motor responses to secretin. Administration of N^G‐nitro‐l ‐arginine methyl ester (10 mg kg^?1) did not affect gastric relaxation induced by secretin. In contrast, intravenous administration of a vasoactive intestinal polypeptide (VIP) antagonist (30 nmol kg^?1) reduced the gastric relaxation response to secretin (5.6 pmol kg^?1 h^?1) by 89 ± 5%. Indomethacin (2 mg kg^?1) reduced gastric relaxation induced by secretin (5.6 pmol kg^?1 h^?1) by 87 ± 5%. Administration of prostaglandin (48 mg kg^?1 h^?1) prevented this inhibitory effect. Indomethacin also reduced gastric relaxation induced by VIP (300 pmol kg^?1) by 90 ± 7%. These observations indicate that secretin acts through stimulation of presynaptic cholinergic neurons in a vagally mediated pathway. Through nicotinic synapses, secretin stimulates VIP release from postganglionic neurons in the gastric myenteric plexus, which in turn induces gastric relaxation through a prostaglandin‐dependent pathway.     

Ghrelin does not stimulate gastrointestinal motility and gastric emptying: an experimental study of conscious dogs

Ghrelin is a peptide that was discovered in endocrine cells of the stomach. However, its action in regulating the fasted and fed motor activity of the digestive tract is not fully understood. In the present study, we examined the effects of an intravenous (i.v.) injection of canine ghrelin on the physiological fasted and fed motor activities in the stomach, duodenum, jejunum and colon of freely moving conscious dogs. An i.v. injection of canine ghrelin released growth hormone in a dose-dependent manner; however, it did not stimulate the motor activity of the digestive tract in either the fasted or the fed state. Moreover, an i.v. injection of high-dose canine ghrelin significantly reduced the motility index in the gastric body in the fasted state. Ghrelin did not accelerate gastric emptying, either. These results differ from previous reports dealing with rodents. It is significant that such results were obtained in research with dogs, which are larger animals.     

Delayed gastric emptying in Parkinson's disease

Gastrointestinal symptoms are evident in all stages of Parkinson's disease (PD). Most of the gastrointestinal abnormalities associated with PD are attributable to impaired motility. At the level of the stomach, this results in delayed gastric emptying. The etiology of delayed gastric emptying in PD is probably multifactorial but is at least partly related to Lewy pathology in the enteric nervous system and discrete brainstem nuclei. Delayed gastric emptying occurs in both early and advanced PD but is underdetected in routine clinical practice. Recognition of delayed gastric emptying is important because it can cause an array of upper gastrointestinal symptoms, but additionally it has important implications for the absorption and action of levodopa. Delayed gastric emptying contributes significantly to response fluctuations seen in people on long‐term l ‐dopa therapy. Neurohormonal aspects of the brain‐gut axis are pertinent to discussions regarding the pathophysiology of delayed gastric emptying in PD and are also hypothesized to contribute to the pathogenesis of PD itself. Ghrelin is a gastric‐derived hormone with potential as a therapeutic agent for delayed gastric emptying and also as a novel neuroprotective agent in PD. Recent findings relating to ghrelin in the context of PD and gastric emptying are considered. This article highlights the pathological abnormalities that may account for delayed gastric emptying in PD. It also considers the wider relevance of abnormal gastric pathology to our current understanding of the etiology of PD. © 2013 International Parkinson and Movement Disorder Society     

Effect of DA‐9701, a novel prokinetic agent,on stress‐induced delayed gastric emptying and hormonal changes in rats

Background DA‐9701 is a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber. This study aimed to evaluate the effect of DA‐9701 on stress‐induced delay in gastric emptying and changes in plasma adrenocorticotropic hormone and ghrelin levels in rats. Methods Changes in gastric emptying in response to different durations of stress were evaluated. Gastric emptying was compared between the following groups: (i) nonstressed vehicle‐ or DA‐9701‐treated group, (ii) nonstressed vehicle‐ or mosapride‐treated group, (iii) 2‐h stressed vehicle‐ or DA‐9701‐treated group, and (iv) 2‐h stressed vehicle‐ or mosapride‐treated group. Water immersion restraint stress was used as the stressor. DA‐9701 or mosapride at 3 mg kg^?1 was administered to the rats after subjecting them to 2‐h stress, and then gastric emptying was measured using the phenol red method. Key Results Gastric emptying was significantly delayed in the 2‐h stressed group compared with the nonstressed group. Mosapride administration resulted in significant recovery from the stress‐induced delay in gastric emptying. Gastric emptying in the rats that underwent 2‐h stress followed by DA‐9701 administration was not significantly different from that in the nonstressed group. The plasma adrenocorticotropic hormone and active ghrelin levels in the 2‐h stressed group were significantly higher than those in the nonstressed group. These increases were significantly inhibited by DA‐9701. Conclusions & Inferences The administration of DA‐9701 improved delayed gastric emptying and inhibited the hormonal changes induced by stress, suggesting that DA‐9701 can be used as a gastroprokinetic agent for the treatment of delayed gastric emptying, particularly that associated with stress.     

Levodopa infusion does not decrease the onset of abnormal involuntary movements in parkinsonian rats

The short duration of effect of levodopa is linked to pulsatile stimulation of striatal dopamine receptors and dyskinesia induction. However, the recent introduction of intraduodenal (i.d.) infusions and novel oral controlled release formulations of l ‐dopa may prevent dyskinesia induction and reduce the severity of established involuntary movements. We have compared the effects of twice‐daily intraperitoneal (i.p.) administration and daily i.d. infusion of l ‐dopa on the induction and expression of abnormal involuntary movements in 6‐hydroxydopamine (6‐OHDA)‐lesioned rats. Animals were treated with either twice‐daily i.p. administration of l ‐dopa/carbidopa (7.85/12.5 mg/kg) or an 8‐hour i.d. infusion of l ‐dopa/carbidopa (20/5 mg/mL; infusion rate: 0.04 mL/h) for 14 days, after which treatments were switched between groups and continued for a further 14 days. Pulsatile i.p. administration of l ‐dopa induced moderate to severe abnormal involuntary movements, which gradually increased in severity over the 14 days, but i.d. infusion of l ‐dopa induced abnormal involuntary movements of a similar severity. Switching from continuous i.d. to pulsatile i.p. administration of l ‐dopa continued to provoke severe abnormal involuntary movements expression. Switching from pulsatile i.p. to continuous i.d. l ‐dopa administration did not alter the peak abnormal involuntary movement severity but tended to reduce their duration. Treatment with less pulsatile l ‐dopa administration using i.d. infusion does not reduce the risk of the appearance of dyskinesia. By contrast, the duration of established dyskinesia can be reduced by more continuous l ‐dopa delivery in agreement with clinical experience. © 2012 Movement Disorder Society     

Contribution of acetylcholine,vasoactive intestinal polypeptide and nitric oxide to CNS-evoked vagal gastric relaxation in the rat

Abstract Several in vitro models of gastric relaxation have elucidated a role of nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) in non-adrenergic, non-cholinergic (NANC) vagally mediated gastric relaxation. However, these models do not necessarily mimic the events leading to gastric relaxation in the whole animal. We have recently described a vagally mediated gastric relaxation evoked by micro-injection of substance P (SP) into the nucleus raphe obscurus (NRO). The present study was performed to elucidate whether this CNS-stimulated in vivo gastric relaxation involved acetylcholine, NO and VIP. Atropine (1 mg kg^?1 i.v.), reduces both the rapid nadir and sustained gastric relaxation evoked by SP in the NRO, and the residual responses are abolished by N^G-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 mg kg^?1 i.v.), an NO synthase inhibitor. Blockade of NO synthase alone is not sufficient to abolish the effect of SP into the NRO on intragastric pressure. A VIP antagonist, [p-chloro-D-Phe⁶, Leu¹⁷]VIP (32 μg i.v.) alone, or with the addition of L-NAME, does not affect the nadir of the gastric relaxation in response to SP microinjected into the NRO; however, both antagonists reduce the CNS-evoked sustained intragastric pressure relaxation. We conclude that, in CNS-evoked gastric relaxation, inhibition of cholinergic pathways is potentially important for both the rapid nadir and sustained gastric relaxation, and both NO and VIP contribute to sustained gastric relaxation.     

Levodopa: A new look at an old friend

Levodopa is the most effective antiparkinsonian agent, but chronic treatment is associated with the development of motor complications in the majority of patients with PD. Recent scientific and clinical advances are improving this situation. Long‐term, double‐blind studies demonstrate that dose is an important risk factor for the development of both motor fluctuations and dyskinesia, and suggest that it is best to use low doses of l ‐dopa when possible. Inhaled l ‐dopa and sublingual apomorphine are now being developed as rescue therapies that permit rapid and predictable reversal of off periods. Finally, substantial evidence suggests that motor complications are related to the nonphysiological restoration of brain dopamine with intermittent oral doses of standard l ‐dopa. Double‐blind studies demonstrate significant clinical benefits with continuous intraintestinal infusion of l ‐dopa. New approaches that provide continuous plasma l ‐dopa levels without the need for a surgical procedure are currently being investigated. Finally, the development of an oral long‐acting form of l ‐dopa that provides continuous plasma l ‐dopa levels is actively being pursued. Collectively, these approaches offer the potential to considerably reduce and even prevent the disability associated with l ‐dopa‐induced motor complications. © 2017 International Parkinson and Movement Disorder Society     

Effect of pulsatile administration of levodopa on dyskinesia induction in drug‐naïve MPTP‐treated common marmosets: Effect of dose,frequency of administration,and brain exposure

Levodopa (L ‐dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine hydrochloride (MPTP) ‐treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L ‐dopa dose and frequency of administration on dyskinesia initiation in drug‐naïve, MPTP‐treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low‐dose of L ‐dopa with the peripheral catechol‐O‐methyltransferase inhibitor (COMT‐I), entacapone. Pulsatile administration of a low (dose range, 5.0–7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L ‐dopa plus carbidopa b.i.d. produced a dose‐related reversal of motor deficits. Repeated administration of low and high doses of L ‐dopa for 26 days to drug‐naïve, MPTP‐treated animals also caused a dose‐related induction of peak‐dose dyskinesia. Repeated administration of high‐dose L ‐dopa b.i.d. compared to once daily caused a frequency‐related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak‐dose dyskinesia. Administration of low‐dose L ‐dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L ‐dopa alone, but with no obvious change in duration of L ‐dopa's effect. However, combining entacapone with L ‐dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L ‐dopa alone. Importantly, increasing pulsatile exposure of brain to L ‐dopa by preventing its peripheral breakdown also increases dyskinesia induction. © 2003 Movement Disorder Society     

Effect of ghrelin and growth hormone-releasing peptide 6 on septic ileus in mice

Ghrelin is an orexigenic peptide with prokinetic effects in the rat. We investigated the effect of ghrelin and growth hormone-releasing hormone 6 (GHRP-6) on gastric emptying and transit in control and septic mice. Mice were injected i.p. with lipopolysaccharides (LPS) or saline (control). After 16-17 h mice were pretreated with saline, ghrelin or GHRP-6 1 h before intragastric administration of Evans blue. Fifteen minutes later, after assessment of the behaviour scale, mice were killed and gastric emptying, transit and rectal temperature were measured. In control mice, ghrelin (100 microg kg(-1)) and GHRP-6 (20-100 microg kg(-1)) accelerated gastric emptying, whereas ghrelin and GHRP-6 failed to increase transit significantly. Septic mice developed a delay in gastric emptying and transit, hypothermia and a deterioration of the behaviour scale. In septic mice, ghrelin (20 microg kg(-1)) accelerated gastric emptying without effect on transit while GHRP-6 significantly accelerated gastric emptying dose-dependently and failed to increase transit significantly. Ghrelin and GHRP-6 had no effect on the endotoxin-induced hypothermia or deterioration of behaviour scale. Therefore, the beneficial prokinetic effect of ghrelin but mainly of GHRP-6 offers potential therapeutic options in the treatment of septic gastric ileus.     

Intralipid-induced gastric relaxation is mediated via NO

In vitro, nitric oxide (NO) has been shown to be the neurotransmitter responsible for gastric relaxation. In vivo gastric relaxations can be controlled via reflex pathways originating in the duodenum. The aim of this study was to determine whether NO was involved in gastric relaxation in vivo in conscious dogs induced by intraduodenal administration of intralipid. Gastric tone was monitored with a flaccid bag introduced into the stomach via a gastric cannula and connected to a barostat. Intralipid administration into the duodenum caused a gastric relaxation (420 ± 11 ml, n = 6) sensitive to inhibition by nitro-L-arginine (L-NNA) (5 mg kg^?1 i.v.). This inhibitory effect of L-NNA was reversed by L-arginine (100 mg kg^?1 i.v.). In conclusion: intraduodenal administration of intralipid induces a gastric relaxation via a NO-dependent mechanism.     

The analgesic effects of the GABAB receptor agonist,baclofen, in a rodent model of functional dyspepsia

Background The amino acid γ‐aminobutyric acid (GABA) is an important modulator of pain but its role in visceral pain syndromes is just beginning to be studied. Our aims were to investigate the effect and mechanism of action of the GABA_B receptor agonist, baclofen, on gastric hypersensitivity in a validated rat model of functional dyspepsia (FD). Methods 10‐day‐old male rats received 0.2 mL of 0.1% iodoacetamide in 2% sucrose daily by oral gavages for 6 days. Control group received 2% sucrose. At 8–10 weeks rats treated with baclofen (0.3, 1, and 3 mg kg^?1 bw) or saline were tested for behavioral and electromyographic (EMG) visceromotor responses; gastric spinal afferent nerve activity to graded gastric distention and Fos protein expression in dorsal horn of spinal cord segments T8–T10 to noxious gastric distention. Key Results Baclofen administration was associated with a significant attenuation of the behavioral and EMG responses (at 1 and 3 mg kg^?1) and expression of Fos in T8 and T9 segments in neonatal iodoacetamide sensitized rats. However, baclofen administration did not significantly affect splanchnic nerve activity to gastric distention. Baclofen (3mg kg^?1) also significantly reduced the expression of spinal Fos in response to gastric distention in control rats to a lesser extent than sensitized rats. Conclusions & Inferences Baclofen is effective in attenuating pain associated responses in an experimental model of FD and appears to act by central mechanisms. These results provide a basis for clinical trials of this drug in FD patients.