Ozaki Masanobu
Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences.
Yakugaku Zasshi. 2016;136(4):591-605. doi: 10.1248/yakushi.15-00265.
The characteristics and functional roles of opioids originally present in vivo (endogenous opioids) in guinea-pig ileum were investigated. The release of endogenous opioids was determined by the inhibitory twitch response evoked by 0.1 Hz stimulation after 10 Hz stimulation (post-tetanic twitch inhibition). The effects of peptidase inhibitors increased the post-tetanic twitch inhibition, prevented by β-funaltrexamine and nor-binaltorphimine, which are selective μ- and κ-opioid receptor subtype antagonists, respectively. Dopamine receptor antagonists (haloperidol, sultopride and domperidone) increased the post-tetanic twitch inhibition. These results suggest that dopamine receptors are involved in modulation of the ileal opioid system, so as to diminish endogenous opioid release by tetanic stimulation, and dopamine antagonists increase the opioid action, that might depend more on the increased release of endogenous opioids. The post-tetanic twitch inhibition was inhibited by adrenalectomy, and showed the supersensitivity of the opioid receptors, resulting from a decrease of endogenous opioids by adrenalectomy. These findings suggest that the increase in morphine-analgesia by adrenalectomy was due to this process. In the presence of naloxone, an opioid antagonist, an increase in basal tension after tetanic stimulation (10 Hz stimulation) (post-tetanic contraction) was observed, and was blocked by spantide, a substance P antagonist, and indomethacin, a prostaglandins-biosynthesis inhibitor. This contraction increased with morphine or peptidase inhibitor exposure, depending on the length of time the ileum was exposed to the morphine or peptidase inhibitor. Post-tetanic contraction might be a useful indicator of the formation of physical dependence to morphine or endogenous opioids in the ileum.
研究了豚鼠回肠中原本存在于体内的阿片类物质（内源性阿片类物质）的特性和功能作用。内源性阿片类物质的释放通过10Hz刺激后0.1Hz刺激诱发的抑制性抽搐反应（强直后抽搐抑制）来确定。肽酶抑制剂的作用增强了强直后抽搐抑制，分别被选择性μ-和κ-阿片受体亚型拮抗剂β-氟纳曲胺和去甲双氢吗啡酮所阻断。多巴胺受体拮抗剂（氟哌啶醇、舒托必利和多潘立酮）增强了强直后抽搐抑制。这些结果表明，多巴胺受体参与回肠阿片系统的调节，从而通过强直刺激减少内源性阿片类物质的释放，而多巴胺拮抗剂增强阿片作用，这可能更多地取决于内源性阿片类物质释放的增加。肾上腺切除术后强直后抽搐抑制受到抑制，并表现出阿片受体的超敏反应，这是由于肾上腺切除术后内源性阿片类物质减少所致。这些发现表明，肾上腺切除术后吗啡镇痛作用的增强是由于这一过程。在阿片拮抗剂纳洛酮存在的情况下，观察到强直刺激（10Hz刺激）后基础张力增加（强直后收缩），并被P物质拮抗剂spantide和前列腺素生物合成抑制剂吲哚美辛所阻断。这种收缩随着吗啡或肽酶抑制剂的暴露而增加，这取决于回肠暴露于吗啡或肽酶抑制剂的时间长度。强直后收缩可能是回肠对吗啡或内源性阿片类物质产生身体依赖性形成的一个有用指标。
