Groth Rachel, Aanonsen Lin
Department of Biology, Macalester College, 1600 Grand Ave, Saint Paul, MN 55105, USA.
Pain. 2002 Nov;100(1-2):171-81. doi: 10.1016/s0304-3959(02)00264-6.
Although known primarily for its role in neuronal development, brain-derived neurotrophic factor (BDNF) has also recently been implicated in processes mediated by the adult nervous system, such as spinal nociception. Peripheral inflammation increases expression of BDNF preferentially in dorsal root ganglion cells that contain substance P and/or calcitonin gene-related peptide, known nociceptive transmitters for which synthesis is also increased during inflammatory states. Expression of the tyrosine kinase receptor that selectively binds BDNF, trkB, is increased in the spinal dorsal horn during inflammation as well. Additionally, intrathecal (i.t.) administration of the BDNF-scavenging protein trkB-IgG attenuates inflammation-induced behavioral responses. Collectively, this evidence implicates BDNF in spinal nociceptive processes. Here we show that, in normal mice, i.t. BDNF produces an acute, dose-dependent thermal hyperalgesic response. Selective inhibition of BDNF expression by i.t. antisense oligodeoxynucleotide treatment produces antinociception in normal mice and attenuates carrageenan-induced hyperalgesia. Further, we demonstrate that i.t. antisense treatment directed against the full-length trkB receptor (trkB.FL) attenuates carrageenan-induced hyperalgesia. Consistent with a trkB.FL-mediated mechanism, the i.t. administration of another trkB ligand, neurotrophin-4/5, also produces hyperalgesia while the trkC agonist neurotrophin-3, which weakly cross-reacts with trkB, has little effect. Finally, with the accumulating evidence linking BDNF to synaptic plasticity, we investigated whether BDNF-induced hyperalgesia in normal mice involves the N-methyl-D-aspartate (NMDA) receptor. Interestingly, i.t. co-administration of the NMDA receptor antagonist D(-)-2-amino-5-phosphonovaleric acid (D-APV) with BDNF dose-dependently inhibits BDNF-induced hyperalgesia, suggesting that BDNF induces acute hyperalgesic responses and affects central sensitization in a process dependent on NMDA receptor activation.
尽管脑源性神经营养因子（BDNF）主要因其在神经元发育中的作用而为人所知，但最近它也被认为参与了由成年神经系统介导的过程，如脊髓痛觉感受。外周炎症优先增加背根神经节细胞中BDNF的表达，这些细胞含有P物质和/或降钙素基因相关肽，它们是已知的伤害性递质，在炎症状态下其合成也会增加。选择性结合BDNF的酪氨酸激酶受体trkB的表达在炎症期间的脊髓背角也会增加。此外，鞘内注射（i.t.）BDNF清除蛋白trkB-IgG可减弱炎症诱导的行为反应。总的来说，这些证据表明BDNF参与了脊髓痛觉感受过程。在这里我们表明，在正常小鼠中，鞘内注射BDNF会产生急性、剂量依赖性的热痛觉过敏反应。通过鞘内注射反义寡脱氧核苷酸处理选择性抑制BDNF表达可在正常小鼠中产生抗伤害感受作用，并减弱角叉菜胶诱导的痛觉过敏。此外，我们证明针对全长trkB受体（trkB.FL）的鞘内反义处理可减弱角叉菜胶诱导的痛觉过敏。与trkB.FL介导的机制一致，鞘内注射另一种trkB配体神经营养因子-4/5也会产生痛觉过敏，而与trkB弱交叉反应的trkC激动剂神经营养因子-3几乎没有作用。最后，随着越来越多的证据将BDNF与突触可塑性联系起来，我们研究了BDNF在正常小鼠中诱导的痛觉过敏是否涉及N-甲基-D-天冬氨酸（NMDA）受体。有趣的是，鞘内同时注射NMDA受体拮抗剂D-(-)-2-氨基-5-磷酸戊酸（D-APV）与BDNF可剂量依赖性地抑制BDNF诱导的痛觉过敏，这表明BDNF诱导急性痛觉过敏反应并在依赖NMDA受体激活的过程中影响中枢敏化。
