Molecular mechanism of changes in the morphine-induced pharmacological actions under chronic pain-like state: suppression of dopaminergic transmission in the brain.
Molecular mechanism of changes in the morphine-induced pharmacological actions under chronic pain-like state: suppression of dopaminergic transmission in the brain.
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DOI：
10.1016/j.lfs.2004.01.006
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发表时间：
2004-04
期刊：
影响因子：
6.1
通讯作者：
M. Narita;Masami Suzuki;S. Imai;Michiko Narita;S. Ozaki;Y. Kishimoto;K. Oe;Y. Yajima;M. Yamazaki;Tsutomu Suzuki
中科院分区：
文献类型：
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作者：
M. Narita;Masami Suzuki;S. Imai;Michiko Narita;S. Ozaki;Y. Kishimoto;K. Oe;Y. Yajima;M. Yamazaki;Tsutomu Suzuki
在本研究中，我们证明了坐骨神经结扎引起的神经病理性疼痛状态是否会导致脊髓上和脊髓细胞内信号的长期变化，这与吗啡的抑制作用有关。坐骨神经结扎的小鼠表现出对吗啡诱导的抗伤害感受的显著抑制。在此条件下，神经结扎小鼠同侧脊髓背角的磷酸化-常规蛋白激酶C样免疫反应性(p-μ-IR)和磷酸化-CPK-阿片受体(p-MOR)-IR明显增强。值得注意的是，在坐骨神经结扎小鼠的这一区域，星形胶质细胞的肥大及其增殖也被注意到。与神经损伤一样，重复吗啡处理后，该区域的cPKC活性和星形胶质细胞肥大/增殖也增加。这些结果提示，坐骨神经结扎引起的脊髓背角cPKC和MOR的磷酸化可能在抑制神经病理性疼痛状态下吗啡的抗伤害性反应中起重要作用。坐骨神经损伤还可显著抑制MOR介导的G蛋白对GABA能神经元的激活和对腹侧被盖区(VTA)多巴胺能神经元ERK活性的显著降低，从而调节阿片类药物的奖赏效应。此外，我们发现，用特定的抑制剂抑制VTA中ERK的级联反应，可以抑制正常小鼠对吗啡的奖赏效应。这些结果表明，VTA内多巴胺能神经元MOR功能的直接降低和ERK活性的持续降低可能有助于抑制神经病理性疼痛状态下吗啡诱导的奖赏效应。总之，我们最近的发现为神经病理性疼痛状态下阿片类药物不敏感的机制提供了新的证据。
In the present study, we demonstrated whether a neuropathic pain-like state induced by sciatic nerve ligation in rodents could cause a long-lasting change in intracellular signaling in both supraspinal and spinal cord related to the suppression of morphine's effect. Mice with sciatic nerve ligation exhibited a significant suppression of the morphine-induced antinociception. Under this condition, phosphorylated-conventional protein kinase C-like immunoreactivity (p-cPKC-IR) and phosphorylated-μ-opioid receptor (p-MOR)-IR were clearly increased on the ipsilateral side in the dorsal horn of the spinal cord of nerve-ligated mice. It is of interest to note that astroglial hypertrophy as well as its proliferation was also noted in this area of sciatic nerve-ligated mice. Like nerve injury, the increase in cPKC activities and astroglial hypertrophy/proliferation in this region was observed by repeated morphine treatment. These findings suggest that the phosphorylation of both cPKC and MOR in the dorsal horn of the spinal cord by sciatic nerve ligation may play a substantial role in the suppression of morphine-induced antinociception under a neuropathic pain-like state. Sciatic nerve injury also caused a significant inhibition of MOR-mediated G-protein activation onto GABAergic neurons and a dramatic reduction in ERK activities onto dopaminergic neurons in the ventral tegmental area (VTA) regulating the rewarding effect of opioids. Furthermore, we found that the inhibition of ERK cascade in the VTA by treatment with specific inhibitors suppressed the morphine-induced rewarding effect in normal mice. These findings provide evidence that the direct reduction in MOR function and the persistent decrease in ERK activity of dopaminergic neurons in the VTA may contribute to the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state. Conclusively, our recent findings provide novel evidences for the mechanism underlying the less sensitivity to opioids under a neuropathic pain-like state.