The possible involvement of dopamine D3 receptors in the regulation of gastric emptying in rats

Yoshikawa, Takashi; Yoshida, Naoyuki

doi:10.1016/j.lfs.2010.09.027

Cited by 8 publications

(7 citation statements)

References 29 publications

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“…The formation of ghrelin/dopamine receptor heterodimers involves D1 receptors and leads to amplification of brain dopamine rewarding processing influencing food intake 69,70 . By contrast, in the present study, ghrelin counteracts a dopamine inhibitory action that could be mainly mediated by D2/D3 receptor subtypes in the periphery 40,41 . The present data point to ghrelin acting through the brain stimulation of gastric cholinergic excitatory pathways 58,71 which are maintained in presence of l ‐dopa thereby preventing the inhibitory effect of dopamine on postsynaptic cholinergic release 42,72 which needs to be assessed in further experiments.…”

Section: Discussionmentioning

confidence: 47%

“…However, a recent in vitro study shows that dopamine at 10 −4 mol L −1 stimulates ghrelin release from mouse ghrelinoma (MGN) 3–1 cells through interaction with the dopamine receptor subtype 1 (D1) 45 . By contrast, D2/D3 receptors are involved in the inhibitory effect of dopamine on gastric motility in rats 40,41,46 . Collectively, these data demonstrate that l ‐dopa/dopamine‐induced delayed gastric transit is not secondary to change in endogenous ghrelin release.…”

Section: Discussionmentioning

confidence: 85%

“…Dopamine reduces spontaneous and stimulated gastric contractions when applied in vitro to a rat stomach organ bath 40 and inhibits gastric emptying and motility when injected i.p. or subcutaneously in fasted rats 40,41 . Dopamine inhibitory action is mimicked by dopamine receptors D2/D3 agonists and may involve peripheral D2/D3 located on post‐ganglionic cholinergic neurons, 5,42 although central mechanisms recruited by l ‐dopa entering into the brain cannot be excluded particularly at the level of brainstem nuclei involved in retching 43 …”

Section: Discussionmentioning

confidence: 99%

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Ghrelin prevents levodopa‐induced inhibition of gastric emptying and increases circulating levodopa in fasted rats

Wang

Murphy

Stengel

et al. 2012

Neurogastroenterology Motil

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Background Levodopa (L-dopa) is the most commonly used treatment for alleviating symptoms of Parkinson's disease. However, L-dopa delays gastric emptying, which dampens its absorption. We investigated whether ghrelin prevents L-dopa action on gastric emptying and enhances circulating L-dopa in rats. Methods Gastric emptying of non-nutrient methylcellulose/phenol red viscous solution was determined in fasted rats treated with orogastric or intraperitoneal (ip) L-dopa, or intravenous (iv) ghrelin 10 min before orogastric L-dopa. Plasma L-dopa and dopamine levels were determined by high pressure liquid chromatography. Plasma acyl ghrelin levels were assessed by radioimmunoassay. Fos expression in the brain was immunostained after iv ghrelin (30 μg kg-1) 10 min before ip L-dopa. Key Results L-dopa (5 and 15 mg kg-1) decreased significantly gastric emptying by 32% and 62% respectively when administered orally, and by 91% and 83% when injected ip. Ghrelin (30 or 100 μg kg-1, iv) completely prevented L-dopa's (15 mg kg-1, orogastrically) inhibitory action on gastric emptying and enhanced plasma L-dopa and dopamine levels compared with vehicle 15 min after orogastric L-dopa. L-dopa (5 mg kg-1) did not modify plasma acyl ghrelin levels at 30 min, 1 and 2 h after iv injection. L-dopa (15 mg kg-1, ip) induced Fos in brain autonomic centers, which was not modified by iv ghrelin. Conclusions & Inferences Ghrelin counteracts L-dopa-induced delayed gastric emptying but not Fos induction in the brain and enhances circulating L-dopa levels. Potential therapeutic benefits of ghrelin agonists in Parkinson's disease patients treated with L-dopa remain to be investigated.

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Section: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Ghrelin prevents levodopa‐induced inhibition of gastric emptying and increases circulating levodopa in fasted rats

Wang

Murphy

Stengel

et al. 2012

Neurogastroenterology Motil

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“…Taken together these data indicate that the coadministration of CD with l -dopa reduces the potency of l -dopa to suppress gastric emptying of non-nutrient meal. This is likely to reflect the decreased formation of dopamine established to suppress gastric emptying through activation of peripheral D2/D3 receptors in rats [20,22,64]. Indeed, the peripheral AADC inhibitor, CD given in conjunction with l -dopa reduces plasma dopamine levels while increasing those of l -dopa measured 30–90 min after their oral administration at 10/1.5 ratio (200/25 mg kg −1 ) in rats [44] and in humans [43].…”

Section: Discussionmentioning

confidence: 99%

Preventive effect of rikkunshito on gastric motor function inhibited by l-dopa in rats

et al. 2014

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We previously reported that ghrelin prevented l-dopa (LD)-induced inhibition of gastric emptying (GE) of a non-nutrient solution in rats. Parkinson’s disease treatment involves the combined administration of l-dopa with the enzyme l-amino acid decarboxylase inhibitor, carbidopa (CD) to reduce peripheral formation of dopamine. We investigated the effect LD/CD given orogastrically (og) on GE of a non-nutrient or nutrient meal and whether og pretreatment with rikkunshito, a kampo medicine clinically used to treat gastroparesis, influenced LD/CD effect on GE and postprandial antral and duodenal motility in conscious rats. LD/CD (20/2 mg kg−1) decreased significantly GE to 26.3 ± 6.0% compared to 61.2 ± 3.2% in og vehicle monitored 20-min after a non-nutrient meal and to 41.9 ± 5.8% compared to 72.9 ± 5.2% in og vehicle monitored 60 min after a nutrient meal. Rikkunshito (0.5 or 1.0 g kg−1) reduced the LD/CD (20/2 mg kg−1) inhibition of GE of non-nutrient meal (36.9 ± 7.4% and 46.6 ± 4.8% respectively vs. 12.1 ± 7.4% in og vehicle plus LD/CD) while having no effect alone (56.6 ± 8.5%). The ghrelin antagonist, [d-Lys3]-GHRP-6 (1 mg kg−1) injected intraperitoneally partially reversed rikkunshito preventive effect on LD/CD-inhibited GE. Rikkunshito (1.0 g kg−1) blocked LD/CD (20/2 mg kg−1)-induced delayed GE of a nutrient meal and the reduction of postprandial antral motility. In 6-hydroxydopamine-induced Parkinson’s disease rat model, rikkunshito (1.0 g kg−1, og) also prevented LD/CD-inhibited gastric emptying of a nutrient meal and enhanced fasting plasma levels of acylated ghrelin. These data indicate that oral rikkunshito alleviates the delayed GE induced by LD/CD in naïve and PD rat model in part through ghrelin-related mechanisms.

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“…Nevertheless, as new chemical entities may have diverse effects on the upper gastrointestinal system, additional and more specific measurements of GE are required. Several methods are available to assess GE in small laboratory animals, but most of the techniques are terminal: stomach removal and weighing, with content analyzed by measuring the radioactivity , counting the number of glass beads remaining in the stomach , or assessing the amount of phenol red remaining in the stomach . The phenol red test can be considered as the historic gold standard and has been extensively investigated in rodents .…”

Section: Discussionmentioning

confidence: 99%

Comparison of the effects of clonidine, loperamide and metoclopramide in two models of gastric emptying in the rat

Goineau

Guillaume

Castagné

2014

Fundamemntal Clinical Pharma

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Several methods are used to evaluate gastric emptying (GE) in rats, which is an important endpoint in preclinical drug development. Although phenol red model or monitoring of plasma acetaminophen levels are well-established procedures for GE assessment, their capacity to detect the effects of pharmacological agents has rarely been compared. This study was therefore designed to evaluate clonidine with loperamide and metoclopramide in the two test models. Rats were administered phenol red or acetaminophen test meals. The remaining amount of phenol red in the stomach or the time course of plasma acetaminophen levels was then measured. In the phenol red test, loperamide (8 mg/kg, p.o.) and clonidine (100 μg/kg, s.c.) decreased GE (-88 and -42%, P < 0.001 and P < 0.01, respectively). Metoclopramide (10 mg/kg, s.c.) accelerated GE (+42%, P < 0.01). Loperamide reduced acetaminophen plasma levels (-45% at T15 min, P < 0.05), suggesting a delayed GE. Clonidine and metoclopramide increased acetaminophen plasma levels (+115 and +152% at T15 min, P < 0.05 and P < 0.001, respectively), suggesting an accelerated GE. The three substances did not affect plasma acetaminophen levels when acetaminophen was subcutaneously injected, thereby suggesting that acetaminophen metabolism/excretion was not modified. Whereas the phenol red test allows the evaluation of GE at a single time point, the measurement of plasma acetaminophen levels over the time would appear more informative. Nevertheless, the fact that clonidine, in contrast to expectation, increased plasma acetaminophen levels, suggests that data obtained with the acetaminophen method should be interpreted with caution for new chemical entities susceptible to modify absorption of acetaminophen from the small intestine.

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The possible involvement of dopamine D3 receptors in the regulation of gastric emptying in rats

Cited by 8 publications

References 29 publications

Ghrelin prevents levodopa‐induced inhibition of gastric emptying and increases circulating levodopa in fasted rats

Ghrelin prevents levodopa‐induced inhibition of gastric emptying and increases circulating levodopa in fasted rats

Preventive effect of rikkunshito on gastric motor function inhibited by l-dopa in rats

Comparison of the effects of clonidine, loperamide and metoclopramide in two models of gastric emptying in the rat

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