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.
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.
Kashyap
Purna
P
Enteric Neuromuscular Disorders and Pain Laboratory, Division of Gastroenterology and Hepatology, University of Texas Medical Branch, Galveston, TX, USA.
Micci
Maria-Adelaide
MA
Pasricha
Sarina
S
Pasricha
Pankaj Jay
PJ
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005746:Gastric Emptying / Q000187:drug effects*; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects*; D009197:Myenteric Plexus / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology*; D011708:Pylorus / Q000187:drug effects* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism
D001578:Benzopyrans; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D009281:Naphthalenes; D010078:Oxazines; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; C097285:nafadotride