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
2
;
Yu CUI
1
;
Li XIAO
2
Author Information
1. Sun Yat-sen University School of Medicine， Shenzhen 518107， China
2. Department of Anesthesiology， The First Affiliated Hospital， Sun Yat-sen University， Guangzhou 510080， China
- Publication Type:Journal Article
- 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:
ObjectiveTo 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. MethodsTwenty 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. ResultsDouble 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. ConclusionsMorphine tolerance is closely related to down-regulation of GIRK1-2 expression and PKCε plays a crucial regulatory role herein.
