Narita Minoru, Suzuki Masami, Imai Satoshi, Narita Michiko, Ozaki Satoru, Kishimoto Yayoi, Oe Kousei, Yajima Yoshinori, Yamazaki Mitsuaki, Suzuki Tsutomu
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
Life Sci. 2004 Apr 9;74(21):2655-73. doi: 10.1016/j.lfs.2004.01.006.
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-micro-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.
在本研究中，我们证明了啮齿动物坐骨神经结扎诱导的神经性疼痛样状态是否会导致与吗啡作用抑制相关的脊髓上和脊髓内细胞内信号传导的长期变化。坐骨神经结扎的小鼠对吗啡诱导的镇痛作用表现出显著抑制。在此条件下，神经结扎小鼠脊髓背角同侧的磷酸化传统蛋白激酶C样免疫反应性（p-cPKC-IR）和磷酸化微阿片受体（p-MOR）-IR明显增加。值得注意的是，在坐骨神经结扎小鼠的该区域也观察到星形胶质细胞肥大及其增殖。与神经损伤一样，重复给予吗啡治疗可观察到该区域cPKC活性增加以及星形胶质细胞肥大/增殖。这些发现表明，坐骨神经结扎导致脊髓背角cPKC和MOR的磷酸化可能在神经性疼痛样状态下抑制吗啡诱导的镇痛作用中起重要作用。坐骨神经损伤还导致中脑腹侧被盖区（VTA）中MOR介导的G蛋白对GABA能神经元的激活受到显著抑制，以及ERK对调节阿片类药物奖赏作用的多巴胺能神经元的活性显著降低。此外，我们发现用特异性抑制剂处理抑制VTA中的ERK级联反应可抑制正常小鼠中吗啡诱导的奖赏作用。这些发现提供了证据，表明VTA中MOR功能的直接降低和多巴胺能神经元ERK活性的持续下降可能导致神经性疼痛样状态下吗啡诱导的奖赏作用受到抑制。总之，我们最近的发现为神经性疼痛样状态下对阿片类药物敏感性降低的潜在机制提供了新的证据。
