Retamal Jeffri, Reyes Andrea, Ramirez Paulina, Bravo David, Hernandez Alejandro, Pelissier Teresa, Villanueva Luis, Constandil Luis
Laboratory of Neurobiology, Department of Biology, Faculty of Chemistry and Biology, University of Santiago de Chile, Santiago, Chile.
Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Santiago, Chile.
Front Pharmacol. 2018 Oct 10;9:1143. doi: 10.3389/fphar.2018.01143. eCollection 2018.
Intrathecal administration of brain derived neurotrophic factor (BDNF) induces long-term potentiation (LTP) and generates long-lasting central sensitization in spinal cord thus mimicking chronic pain, but the relevance of these observations to chronic pain mechanisms is uncertain. Since C-fiber activation by a high-frequency subcutaneous electrical stimulation (SES) protocol causes spinal release of BDNF and induces spinal cord LTP, we propose that application of such protocol would be a sufficient condition for generating long-lasting BDNF-mediated central sensitization. Results showed that application of burst-like SES to rat toes produced (i) rapid induction of hyperalgesia that lasted for more than 3 weeks, (ii) early increase of C-reflex activity followed by increased wind-up scores lasting for more than 1 week, and (iii) early increase followed by late decrease in BDNF protein levels and phosphorylated TrkB that lasted for more than 1 week. These changes were prevented by the TrkB antagonist cyclotraxin-B administered shortly before SES, while hyperalgesia was reversed by cyclotraxin-B administered 3 days after SES. Results suggest that mechanisms underlying central sensitization first involve BDNF release of probably neuronal origin, followed by brief increased expression of likely glial BDNF and pTrkB that could switch early phase sensitization into late one.
鞘内注射脑源性神经营养因子（BDNF）可诱导长时程增强（LTP），并在脊髓中产生持久的中枢敏化，从而模拟慢性疼痛，但这些观察结果与慢性疼痛机制的相关性尚不确定。由于高频皮下电刺激（SES）方案激活C纤维会导致脊髓释放BDNF并诱导脊髓LTP，我们提出应用该方案将是产生持久的BDNF介导的中枢敏化的充分条件。结果表明，对大鼠脚趾施加爆发样SES会产生：（i）快速诱导持续超过3周的痛觉过敏，（ii）C反射活动早期增加，随后卷绕分数增加持续超过1周，以及（iii）BDNF蛋白水平和磷酸化TrkB早期增加，随后晚期降低，持续超过1周。在SES之前不久给予TrkB拮抗剂环曲菌素-B可防止这些变化，而在SES后3天给予环曲菌素-B可逆转痛觉过敏。结果表明，中枢敏化的潜在机制首先涉及可能源自神经元的BDNF释放，随后可能是胶质细胞BDNF和pTrkB的短暂表达增加，这可能会将早期敏化转变为晚期敏化。
