Morphine Induces Antinociceptive Tolerance and Down-regulation of GIRK1-2 Expression in Rats
10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).20240907.011
- VernacularTitle:吗啡诱导大鼠镇痛耐受和脊髓GIRK1-2表达减少
- Author:
Qiaorui YANG
1
;
Xiao-E WANG
;
Yu CUI
;
Li XIAO
Author Information
1. 中山大学医学院,广东 深圳 518107
- Keywords:
morphine;
tolerance;
G protein-gated inwardly-rectifying potassium 1;
G protein-gated inwardly-rectifying potassium 2;
protein kinase C-ε
- From:
Journal of Sun Yat-sen University(Medical Sciences)
2024;45(5):701-708
- CountryChina
- Language:Chinese
-
Abstract:
[Objective]To observe the expression of spinal G protein-gated inwardly-rectifying potassium(GIRK)channel subunits 1 and 2 in spinal dorsal horn of morphine-tolerant rats and investigate the regulatory mechanism.[Methods]Twenty four rats were equally and randomly divided into 4 groups:saline,morphine,morphine+saline and morphine+εV1-2.The morphine-tolerant rat model was established by intrathecal administration of morphine(15 μg/d)for 7 days.Thirty minutes before daily morphine administration,rats received protein kinase C-ε(PKCε)selective inhibitor εV1-2 to test its effect on morphine tolerance and GIRK1-2 expression.All rats received behavioral tests on days 1,3,5 and 7 and thereafter immunofluorescence.[Results]Double fluorescence staining showed that GIRK1 and GIRK2 were expressed primarily in the spinal laminae I-Ⅱ and co-immunostained with μ-opioid receptor(MOR).Seven-day intrathecal administration of morphine induced antinociceptive tolerance and a significant reduction of the spinal GIRK1(22.45±10.58 vs.62.83±20.80,P<0.001)and GIRK2(23.67±8.78 vs.50.17±11.05,P=0.001)fluorescence intensity,as compared with saline control rats.In addition,pretreatment with εV1-2 significantly delayed the reduction of morphine antinociception(P<0.001)and prevented the decrease of GIRK1(54.50±10.37 vs.19.33±9.48,P<0.001)and GIRK2(39.83±6.24 vs.15.83±9.58,P=0.001)expression induced by morphine treatment.[Conclusions]Morphine tolerance is closely related to down-regulation of GIRK1-2 expression and PKCε plays a crucial regulatory role herein.
