胍丁胺通过抑制大鼠脊髓JNK通路对抗慢性吗啡耐受

目的探讨脊髓c-Jun蛋白氨基末端激酶(c-Jun N-ter-minal kinase,JNK)在胍丁胺抗慢性吗啡镇痛耐受中的作用。方法 SD大鼠皮下注射吗啡(10 mg.kg-1,每日2次,连续9 d)建立慢性吗啡镇痛耐受模型。应用热水甩尾法测定甩尾潜伏期观察吗啡的镇痛效果。应用免疫印迹法(Westernblot)检测脊髓总JNK和磷酸化(p)-JNK蛋白表达;免疫组织化学染色法检测脊髓p-JNK的免疫反应性(immnunoreac-tivity,IR)。结果吗啡耐受大鼠脊髓背角p-JNK-IR明显增多,p-JNK蛋白表达也增多,而总JNK没有改变。胍丁胺(10 mg.kg-1)不仅拮抗吗啡镇痛耐受,而且明显地抑制脊髓背角p-JNK-IR增多及p-JNK蛋白表达上调。结论抑制慢性吗啡注射所引起的脊髓JNK的激活可能是胍丁胺抗吗啡镇痛耐受的作用机制之一。

Agmatine blocks chronic morphine antinociceptive tolerance by inhibiting spinal JNK pathway in rats

Aim To investigate role of the spinal c-Jun N-terminal kinase(JNK) in attenuation of morphine tolerance to analgesia by agmatine.Methods Morphine antinociceptive tolerance was induced by subcutaneous(s.c.) injection of morphine(10 mg·kg-1) twice daily for 9 consecutive days in the adult Sprague-Dawley rats.The analgesia effect was assessed by hot-water tail flick test.The expression of total JNK and phosphorylated(p)-JNK were detected by Western blot assay.Immunoreactivity(IR) of p-JNK in the spinal dorsal horn was tested by immunohistochemistry assay.Results The p-JNK-IR and p-JNK protein expression increased in the spinal dorsal horn of chronic morphine antinociceptive tolerance rats.Agmatine(10 mg·kg-1) not only blocked morphine antinociceptive tolerance,but also significantly attenuated the increases in p-JNK-IR and p-JNK protein expression in the spinal dorsal horn.Conclusion Inhibition of chronic morphine-induced spinal JNK activation may be one of the mechanisms underlying the blockage of morphine antinociceptive tolerance by agmatine.