Departamento de Farmacobiología, Cinvestav, Sede Sur, Mexico City, Mexico.
Behav Brain Res. 2021 Sep 10;413:113446. doi: 10.1016/j.bbr.2021.113446. Epub 2021 Jul 3.
TREK-1 channels are expressed in small nociceptive dorsal root ganglion (DRG) neurons where they participate in acute inflammatory and neuropathic pain. However, the role of TREK-1 in persistent pain is not well understood. The aim of this study was to investigate the local peripheral and spinal participation of TREK-1 in formalin-induced acute and long-lasting nociceptive hypersensitivity. Local peripheral or intrathecal pre-treatment with spadin, selective blocker of TREK-1, increased acute flinching behavior and secondary mechanical allodynia and hyperalgesia behavior observed 6 days after formalin injection. Local peripheral or intrathecal pre-treatment with BL-1249, selective opener of TREK-1, decreased long-lasting secondary mechanical allodynia and hyperalgesia induced by formalin. Pre-treatment with BL-1249 prevented the pro-nociceptive effect of spadin on acute nociception and long-lasting mechanical allodynia and hyperalgesia in rats. Pre-treatment with two recombinant channels that produce a high TREK-1 current, S300A and S333A (non-phosphorylated state of TREK-1), reduced formalin-induced acute pain and long-lasting mechanical allodynia and hyperalgesia. Besides, post-treatment with S300A, S333A or BL-1249 reversed long-lasting mechanical allodynia and hyperalgesia induced by formalin. Formalin increased TREK-1 expression at 1 and 6 days in DRG and dorsal spinal cord in rats, whereas that it increased c-fos expression at the DRG. Intrathecal repeated transfection of rats with S300A and S333A or injection with BL-1249 reduced formalin-induced enhanced c-fos expression. Data suggest that TREK-1 activity at peripheral and spinal sites reduces neuronal excitability in the process of acute and long-lasting nociception induced by formalin in rats.
TREK-1 通道在小的伤害感受性背根神经节 (DRG) 神经元中表达，在那里它们参与急性炎症和神经病理性疼痛。然而，TREK-1 在持续性疼痛中的作用尚不清楚。本研究旨在研究 TREK-1 在福尔马林诱导的急性和慢性痛觉过敏中的局部外周和脊髓参与。局部外周或鞘内预先给予 spadin（TREK-1 的选择性阻断剂）增加了福尔马林注射后 6 天观察到的急性畏缩行为和继发性机械性痛觉过敏和痛觉超敏。局部外周或鞘内预先给予 BL-1249（TREK-1 的选择性开放剂）降低了福尔马林诱导的慢性继发性机械性痛觉过敏和痛觉超敏。BL-1249 预处理可预防 spadin 对急性痛觉和慢性机械性痛觉过敏和痛觉超敏的促伤害作用。两种产生高 TREK-1 电流的重组通道 S300A 和 S333A（TREK-1 的非磷酸化状态）预处理降低了福尔马林诱导的急性疼痛和慢性机械性痛觉过敏和痛觉超敏。此外，S300A、S333A 或 BL-1249 的后期处理逆转了福尔马林诱导的慢性机械性痛觉过敏和痛觉超敏。福尔马林在大鼠 DRG 和背根脊髓中于第 1 天和第 6 天增加 TREK-1 表达，而在 DRG 中增加 c-fos 表达。大鼠鞘内重复转染 S300A 和 S333A 或注射 BL-1249 降低了福尔马林诱导的 c-fos 表达增强。数据表明，TREK-1 在大鼠福尔马林诱导的急性和慢性痛觉过敏过程中的外周和脊髓部位的活性降低了神经元的兴奋性。
