Actions of domperidone on the opioid system in isolated guinea‐pig ileum: differences between dopamine antagonists on opioid system

Abstract

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.

Pharmacological Differences between Liu-Jun-Zi-Tang, a Traditional Chinese Herbal Medicine, and Domperidone on Isolated Guinea-Pig Ileum

“…Therefore, the effects of Liu-Jun-Zi-Tang on ACh-induced contraction of basal tension, an indicator of direct action on the ACh receptor, was investigated. Additionally, it has been reported by us that domperidone similarly showed inhibition of the 0.1 Hz-evoked twitch response, 16) and that the ACh-induced contraction was inhibited with non-competitive manner in the presence of 1 mg/ml Liu-Jun-Zi-Tang (Fig. 3) or domperidone, 16) although even 0.1 mg/ml Liu-Jun-Zi-Tang may inhibit the release of ACh, since the ACh-induced contraction was not influenced but the twitch response was inhibited.…”

“…Additionally, it has been reported by us that domperidone similarly showed inhibition of the 0.1 Hz-evoked twitch response, 16) and that the ACh-induced contraction was inhibited with non-competitive manner in the presence of 1 mg/ml Liu-Jun-Zi-Tang (Fig. 3) or domperidone, 16) although even 0.1 mg/ml Liu-Jun-Zi-Tang may inhibit the release of ACh, since the ACh-induced contraction was not influenced but the twitch response was inhibited. These findings indicate that Liu-Jun-Zi-Tang and domperidone inhibit not only the release of ACh from the cholinergic neuron but also contractile effects by various drugs on the ileal smooth muscle.…”

“…Each concentration of ACh was cumulatively applied in the presence and absence of Liu-Jun-Zi-Tang (0.05, 0.1, 1 mg/ml), which had been previously replaced, or domperidone (1, 10, 20, 100 mM), and added at a volume of 5 ml before 10 min, as we previously reported. 16) Effects of Liu-Jun-Zi-Tang and Domperidone on ACh-, Histamine-and Barium Chloride-Induced Basal Contraction Electrical field stimulation was stopped and ACh (10 Ϫ7 M), histamine (5ϫ10 Ϫ7 M) and barium chloride (10 Ϫ4 M), at which concentrations they induce submaximal contraction of the muscle, were added to the bath, respectively. Domperidone was added to the bath at the volume of 10 ml, and ACh, histamine and barium chloride were added in volumes of 5, 5 and 50 ml, respectively.…”

“…16) Various concentrations of domperidone were added singly to a bath with a volume of 5 ml of each concentration, then equilibrated with continuous stimulation (stimulated for about 40 min) until a stable twitch response was obtained. The application of domperidone was performed between 40 and 50 min after setting the preparation.…”

The analgesic activity of Bestatin as a potent APN inhibitor

“…It's already known that chronic administration of morphine can induce tolerance and dependence, exhibiting a characteristic abstinence syndrome during the challenge of naloxone (NLX), an opioid antagonist, which can antagonize the antinociception of all the endogenous opioid ligands. Ozaki et al (1994) firstly discovered that Bestatin could increase the ileal twitch inhibitory potency caused by ME as well as transient inhibition of twitch contraction after tetanic stimulation. These results suggested that Bestatin-sensitive aminopeptidase participated in the post-tetanic twitch inhibition.…”