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通过诱导大鼠μ-阿片受体胞吞作用增强吗啡镇痛效果。

Enhancement of morphine analgesic effect with induction of mu-opioid receptor endocytosis in rats.

作者信息

Hashimoto Tatsuya, Saito Yoji, Yamada Kazuo, Hara Nobumasa, Kirihara Yumiko, Tsuchiya Mikako

机构信息

Department of Anesthesiology, Shimane University Faculty of Medicine, Japan.

出版信息

Anesthesiology. 2006 Sep;105(3):574-80. doi: 10.1097/00000542-200609000-00023.

Abstract

BACKGROUND

Morphine can desensitize mu-opioid receptor (MOR), but it does not cause internalization of the receptor after binding. Acute desensitization of MOR impairs the efficiency of signaling, whereas the receptor internalization restores the cell responsiveness to the agonists. Thereby, the property of morphine may limit the analgesic effects of this opiate drug. It has been shown that [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), a potent MOR agonist inducing the internalization, facilitates morphine to internalize MOR, suggesting that MOR agonists with low relative activity versus endocytosis (RAVE) values such as DAMGO can potentiate analgesic effects of morphine through stimulating MOR internalization. The authors examined whether the acute analgesic effect of morphine can be potentiated by low relative activity versus endocytosis agonists DAMGO and fentanyl.

METHODS

Rats injected intrathecally with opioids were subjected to a hot plate test for antinociceptive effect. Immunostained spinal dorsal horn was analyzed by confocal microscopy.

RESULTS

Fentanyl induced MOR internalization to a lesser extent than DAMGO at equianalgesic doses. Coadministration of fentanyl promoted morphine-induced MOR internalization. The analgesic effect of morphine was greatly potentiated together with decrease in the relative activity versus endocytosis value when MOR internalization was induced by coadministration of a subanalgesic dose of DAMGO or fentanyl. In contrast, the combination of DAMGO and fentanyl increased neither the analgesic effect nor the internalization of MOR.

CONCLUSIONS

The results suggest that the coadministration of morphine with MOR-internalizing agonist is clinically applicable to develop successful pain-management regimens to achieve satisfactory analgesia using less morphine.

摘要

背景

吗啡可使μ-阿片受体(MOR)脱敏,但结合后不会导致该受体内化。MOR的急性脱敏会损害信号传导效率,而受体内化可恢复细胞对激动剂的反应性。因此,吗啡的这种特性可能会限制这种阿片类药物的镇痛效果。研究表明,[D-丙氨酸2,甲硫氨酸苯丙氨酸4,甘醇5]脑啡肽(DAMGO)是一种能诱导受体内化的强效MOR激动剂,它能促进吗啡使MOR内化,这表明相对内吞活性(RAVE)值较低的MOR激动剂(如DAMGO)可通过刺激MOR内化来增强吗啡的镇痛效果。作者研究了相对内吞活性较低的激动剂DAMGO和芬太尼是否能增强吗啡的急性镇痛作用。

方法

鞘内注射阿片类药物的大鼠接受热板试验以检测镇痛效果。通过共聚焦显微镜分析免疫染色的脊髓背角。

结果

在等效镇痛剂量下,芬太尼诱导MOR内化的程度低于DAMGO。芬太尼与吗啡联合给药可促进吗啡诱导的MOR内化。当联合给予亚镇痛剂量的DAMGO或芬太尼诱导MOR内化时,吗啡的镇痛效果显著增强,同时相对内吞活性值降低。相比之下,DAMGO和芬太尼联合使用既未增强镇痛效果,也未增加MOR的内化。

结论

结果表明,吗啡与能使MOR内化的激动剂联合给药在临床上适用于制定成功的疼痛管理方案,以使用更少的吗啡实现满意的镇痛效果。

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