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The D2/D3 Agonist PD128907 (R-(+)-trans-3,4a,10b-Tetrahydro-4-Propyl-2H,5H-[1]Benzopyrano[4,3-b]-1,4-Oxazin-9-ol) Inhibits Stimulated Pyloric Relaxation and Spontaneous Gastric Emptying

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Abstract

Background Enteric neuronal dopamine (DA) inhibits acetylcholine release and gastric motility; this has been thought to be mediated via neuronal dopamine-2 receptor (D2R). The aim of this study was to investigate the modulation of gastric motility by the dopamine-3 receptor (D3R). Methods Adult Sprague–Dawley rats were used. Pyloric relaxation in response to electrical field stimulation (EFS) was assessed in an organ bath in the presence of varying concentrations of a selective D3R agonist, PD128907. Gastric emptying was assessed by the phenol red method after rats were treated with varying doses of PD128907 or DA with and without a selective D3R antagonist, l-nafadotride. Results Immunoblotting and immunohistochemistry confirmed the presence of D3R in the myenteric neurons in the rat pylorus. D3R activation reduced EFS-induced relaxation of pyloric strips in a dose-dependent manner and significantly delayed gastric emptying compared with vehicle. The D3R antagonist partially reversed the effect of DA on gastric emptying. Conclusions Our data suggest a novel role for D3R in regulation of gastric motility. D3R activation delays gastric emptying, an effect that may be due to impairment of pyloric relaxation. D3R antagonists therefore hold promise as useful agents for treatment of gastric motility disorders.

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References

  1. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146–151. doi:10.1038/347146a0

    Article  PubMed  CAS  Google Scholar 

  2. Sunahara RK et al (1991) Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1. Nature 350:614–619. doi:10.1038/350614a0

    Article  PubMed  CAS  Google Scholar 

  3. Van Tol HH et al (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614. doi:10.1038/350610a0

    Article  PubMed  Google Scholar 

  4. Tougas G, Anvari M, Dent J, Somers S, Richards D, Stevenson GW (1992) Relation of pyloric motility to pyloric opening and closure in healthy subjects. Gut 33(4):466–471. doi:10.1136/gut.33.4.466

    Article  PubMed  CAS  Google Scholar 

  5. Scarpignato C, Capovilla T, Bertaccini G (1980) Action of caerulein on gastric emptying of the conscious rat. Arch Int Pharmacodyn Ther 246:286–294

    PubMed  CAS  Google Scholar 

  6. Giros B, Martres MP, Pilon C, Sokoloff P, Schwartz JC (1991) Shorter variants of the D3 dopamine receptor produced through various patterns of alternative splicing. Biochem Biophys Res Commun 176:1584–1592. doi:10.1016/0006-291X(91)90469-N

    Article  PubMed  CAS  Google Scholar 

  7. Snyder LA, Roberts JL, Sealfon SC (1991) Alternative transcripts of the rat and human dopamine D3 receptor. Biochem Biophys Res Commun 180:1031–1035. doi:10.1016/S0006-291X(05)81169-6

    Article  PubMed  CAS  Google Scholar 

  8. Werkman TR, Glennon JC, Wadman WJ, McCreary AC (2006) Dopamine receptor pharmacology: interactions with serotonin receptors and significance for the aetiology and treatment of schizophrenia. CNS Neurol Disord Drug Targets 5:3–23

    Article  PubMed  CAS  Google Scholar 

  9. Li ZS, Pham TD, Tamir H, Chen JJ, Gershon MD (2004) Enteric dopaminergic neurons: definition, developmental lineage, and effects of extrinsic denervation. J Neurosci 24:1330–1339. doi:10.1523/JNEUROSCI.3982-03.2004

    Article  PubMed  CAS  Google Scholar 

  10. Anlauf M, Schafer MK, Eiden L, Weihe E (2003) Chemical coding of the human gastrointestinal nervous system: cholinergic, VIPergic, and catecholaminergic phenotypes. J Comp Neurol 459:90–111. doi:10.1002/cne.10599

    Article  PubMed  CAS  Google Scholar 

  11. Kurosawa S, Hasler WL, Torres G, Wiley JW, Owyang C (1991) Characterization of receptors mediating the effects of dopamine on gastric smooth muscle. Gastroenterology 100:1224–1231

    PubMed  CAS  Google Scholar 

  12. Takahashi T, Kurosawa S, Wiley JW, Owyang C (1991) Mechanism for the gastrokinetic action of domperidone. In vitro studies in guinea pigs. Gastroenterology 101:703–710

    PubMed  CAS  Google Scholar 

  13. Reddymasu SC, Soykan I, McCallum RW (2007) Domperidone: review of pharmacology and clinical applications in gastroenterology. Am J Gastroenterol 102(9):2036–2045

    Article  PubMed  CAS  Google Scholar 

  14. Moreland RB et al (2004) Comparative pharmacology of human dopamine D(2)-like receptor stable cell lines coupled to calcium flux through Galpha(qo5). Biochem Pharmacol 68:761–772. doi:10.1016/j.bcp.2004.05.019

    Article  PubMed  CAS  Google Scholar 

  15. Tonini M et al (2004) Review article: clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. Aliment Pharmacol Ther 19:379–390. doi:10.1111/j.1365-2036.2004.01867.x

    Article  PubMed  CAS  Google Scholar 

  16. Li ZS, Schmauss C, Cuenca A, Ratcliffe E, Gershon MD (2006) Physiological modulation of intestinal motility by enteric dopaminergic neurons and the D2 receptor: analysis of dopamine receptor expression, location, development, and function in wild-type and knock-out mice. J Neurosci 26:2798–2807. doi:10.1523/JNEUROSCI.4720-05.2006

    Article  PubMed  CAS  Google Scholar 

  17. Sautel F et al (1995) Nafadotride, a potent preferential dopamine D3 receptor antagonist, activates locomotion in rodents. J Pharmacol Exp Ther 275:1239–1246

    PubMed  CAS  Google Scholar 

  18. Levant B, Vansell NR (1997) In vivo occupancy of D2 dopamine receptors by nafadotride. Neuropsychopharmacology 17:67–71. doi:10.1016/S0893-133X(97)00024-9

    Article  PubMed  CAS  Google Scholar 

  19. Sammut S, Bray KE, West AR (2007) Dopamine D2 receptor-dependent modulation of striatal NO synthase activity. Psychopharmacology (Berl) 191:793–803. doi:10.1007/s00213-006-0681-z

    Article  CAS  Google Scholar 

  20. Yoshida N, Yoshikawa T, Hosoki K (1995) A dopamine D3 receptor agonist, 7-OH-DPAT, causes vomiting in the dog. Life Sci 57:PL347–PL350. doi:10.1016/0024-3205(95)02186-M

    Article  PubMed  CAS  Google Scholar 

  21. Yoshikawa T, Yoshida N, Hosoki K (1996) Involvement of dopamine D3 receptors in the area postrema in R(+)-7-OH-DPAT-induced emesis in the ferret. Eur J Pharmacol 301:143–149. doi:10.1016/0014-2999(96)00061-1

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Pankaj Jay Pasricha.

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Kashyap, P., Micci, MA., Pasricha, S. et al. The D2/D3 Agonist PD128907 (R-(+)-trans-3,4a,10b-Tetrahydro-4-Propyl-2H,5H-[1]Benzopyrano[4,3-b]-1,4-Oxazin-9-ol) Inhibits Stimulated Pyloric Relaxation and Spontaneous Gastric Emptying. Dig Dis Sci 54, 57–62 (2009). https://doi.org/10.1007/s10620-008-0335-6

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