Yajima Yoshinori, Narita Minoru, Usui Aiko, Kaneko Chihiro, Miyatake Mayumi, Narita Michiko, Yamaguchi Takanori, Tamaki Hiroko, Wachi Hiroshi, Seyama Yoshiyuki, Suzuki Tsutomu
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
J Neurochem. 2005 May;93(3):584-94. doi: 10.1111/j.1471-4159.2005.03045.x.
Thermal hyperalgesia and tactile allodynia induced by sciatic nerve ligation were completely suppressed by repeated intrathecal (i.t.) injection of a TrkB/Fc chimera protein, which sequesters endogenous brain-derived neurotrophic factor (BDNF). In addition, BDNF heterozygous (+/-) knockout mice exhibited a significant suppression of nerve ligation-induced thermal hyperalgesia and tactile allodynia compared with wild-type mice. After nerve ligation, BDNF-like immunoreactivity on the superficial laminae of the ipsilateral side of the spinal dorsal horn was clearly increased compared with that of the contralateral side. It should be noted that a single i.t. injection of BDNF produced a long-lasting thermal hyperalgesia and tactile allodynia in normal mice, and these responses were abolished by i.t. pre-treatment with either a Trk-dependent tyrosine kinase inhibitor K-252a or a selective protein kinase C (PKC) inhibitor Ro-32-0432. Supporting these findings, we demonstrated here for the first time that the increase in intracellular Ca2+ concentration by application of BDNF in cultured mouse spinal neurons was abolished by pre-treatment with either K-252a or Ro-32-0432. Taken together, these findings suggest that the binding of spinally released BDNF to TrkB by nerve ligation may activate PKC within the spinal cord, resulting in the development of a neuropathic pain-like state in mice.
坐骨神经结扎诱导的热痛觉过敏和触觉异常性疼痛，通过反复鞘内注射TrkB/Fc嵌合蛋白（该蛋白可隔离内源性脑源性神经营养因子（BDNF））而被完全抑制。此外，与野生型小鼠相比，BDNF杂合子（+/-）基因敲除小鼠的神经结扎诱导的热痛觉过敏和触觉异常性疼痛明显受到抑制。神经结扎后，与对侧相比，脊髓背角同侧浅层的BDNF样免疫反应性明显增加。值得注意的是，单次鞘内注射BDNF可在正常小鼠中产生持久的热痛觉过敏和触觉异常性疼痛，而这些反应可通过鞘内预先用Trk依赖性酪氨酸激酶抑制剂K-252a或选择性蛋白激酶C（PKC）抑制剂Ro-32-0432预处理而消除。支持这些发现的是，我们首次证明，在培养的小鼠脊髓神经元中，通过预先用K-252a或Ro-32-0432预处理，可消除应用BDNF引起的细胞内Ca2+浓度升高。综上所述，这些发现表明，神经结扎后脊髓释放的BDNF与TrkB的结合可能激活脊髓内的PKC，导致小鼠出现神经性疼痛样状态。
