Yajima Yoshinori, Narita Minoru, Narita Michiko, Matsumoto Nozomi, Suzuki Tsutomu
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Brain Res. 2002 Dec 27;958(2):338-46. doi: 10.1016/s0006-8993(02)03666-1.
Partial sciatic nerve ligation in mice caused a marked and persistent decrease in the latency of paw withdrawal from a thermal stimulus only on the ipsilateral side. This thermal hyperalgesia was abolished by repeated intrathecal pretreatment with a specific antibody to brain-derived neurotrophic factor (BDNF), but not neurotrophin-4, just before and after the nerve ligation. These results provide direct evidence that BDNF within the spinal cord may contribute to the development of thermal hyperalgesia caused by nerve injury in mice. We previously reported that protein level of full-length TrkB, which contains the cytoplasmic protein tyrosine kinase domain, were clearly increased on the ipsilateral side of spinal cord membranes obtained from sciatic nerve-ligated mice. In the present study, we further demonstrated that the increased in the protein level of full-length TrkB is completely reversed by concomitant intrathecal injection of BDNF antibody. Furthermore, thermal hyperalgesia induced by nerve ligation was completely suppressed by repeated intrathecal injection of a specific antibody to full-length TrkB and an inhibitor of the protein tyrosine kinase activity for the neurotrophin receptor, K-252a. However, repeated intrathecal injection of a specific antibody to truncated TrkB, which lacks the cytoplasmic protein tyrosine kinase domain, failed to reverse thermal hyperalgesia observed in nerve-ligated mice. These findings suggest the possibility that the binding of BDNF to full-length TrkB and subsequent its activation may play a critical role in the development of neuropathic pain-like thermal hyperalgesia induced by nerve injury in mice.
小鼠坐骨神经部分结扎仅导致同侧爪对热刺激的缩爪潜伏期显著且持续降低。在神经结扎前后，通过鞘内反复预处理脑源性神经营养因子（BDNF）特异性抗体可消除这种热痛觉过敏，但神经营养蛋白-4特异性抗体则无效。这些结果提供了直接证据，表明脊髓内的BDNF可能参与了小鼠神经损伤所致热痛觉过敏的发生。我们之前报道，包含胞质蛋白酪氨酸激酶结构域的全长TrkB蛋白水平在坐骨神经结扎小鼠脊髓膜的同侧明显升高。在本研究中，我们进一步证明，鞘内注射BDNF抗体可完全逆转全长TrkB蛋白水平的升高。此外，神经结扎诱导的热痛觉过敏可通过鞘内反复注射全长TrkB特异性抗体和神经营养因子受体蛋白酪氨酸激酶活性抑制剂K-252a完全抑制。然而，鞘内反复注射缺乏胞质蛋白酪氨酸激酶结构域的截短型TrkB特异性抗体未能逆转神经结扎小鼠中观察到的热痛觉过敏。这些发现提示，BDNF与全长TrkB的结合及其随后的激活可能在小鼠神经损伤诱导的神经性疼痛样热痛觉过敏的发生中起关键作用。
