Actions of domperidone on the opioid system in isolated guinea-pig ileum: differences between dopamine antagonists on opioid system.
1. To validate the relationship between the dopaminergic, opioidergic and cholinergic nervous systems, we evaluated the effect of domperidone, a dopamine (D2) antagonist, on the opioid system in myenteric plexus-longitudinal muscle preparation isolated from the guinea-pig ileum. 2. One micromolar of domperidone did not affect the 0.1 Hz-evoked (duration 0.5 ms, maximum intensity) twitch response, but concentration dependently inhibited the twitch response between concentrations of 2 and 20 microM, and the inhibition was maximum after 20-30 min at the highest concentration used (20 microM). 3. Acetylcholine-evoked contraction on basal tension was also not inhibited by 1 microM domperidone, but the contraction was concentration dependently inhibited at concentrations of 10-100 microM in a non-competitive manner. 4. One micromolar of domperidone, however, increased post-tetanic twitch inhibition, an indicator of the release of endogenous opioids. This increase was completely antagonized by 1 microM naloxone. Twitch inhibition induced by dynorphin 1-13 (0.1-10 nM) was not affected by 1 microM domperidone, but increased the maximum twitch inhibition caused by morphine (0.1-1 microM). 6. These results might reflect the existence of an interaction between the dopaminergic and opioidergic system without the inhibition of the cholinergic system. Dopamine antagonists increased opioid action, an action that may depend more on the increased release of endogenous opioids than on supersensitivity of the opioid receptor.
Ozaki
M
M
Department of Toxicology, Faculty of Pharmacy, Niigata University of Pharmacy and Applied Life Sciences, Niigata 950-2076, Japan.
Masuda
Y
Y
Kishioka
S
S
Yamamoto
H
H
D000818:Animals; D004294:Domperidone / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D011957:Receptors, Opioid / Q000502:physiology*
D018492:Dopamine Antagonists; D011957:Receptors, Opioid; D004294:Domperidone