1 Department of Neural and Pain Sciences, School of Dentistry, University of Maryland, Baltimore, MD, USA.
2 Program in Neuroscience, University of Maryland, Baltimore, MD, USA.
Mol Pain. 2019 Jan-Dec;15:1744806918825044. doi: 10.1177/1744806918825044.
The glutamate type 1 transporter (GLT1) plays a major role in glutamate homeostasis in the brain. Although alterations of GLT1 activity have been linked to persistent pain, the significance of these changes is poorly understood. Focusing on the rostral ventromedial medulla, a key site in pain modulation, we examined the expression and function of GLT1 and related transcription factor kappa B-motif binding phosphoprotein (KBBP) in rats after adjuvant-induced hind paw inflammation.
After inflammation, GLT1 and KBBP showed an early upregulation and gradual transition to downregulation that lasted throughout the eight-week observation period. Nitration of GLT1 was reduced at 30 min and increased at eight weeks after inflammation, suggesting an initial increase and later decrease in transporter activity. Mechanical hyperalgesia and paw edema exhibited an initial developing phase with peak hyperalgesia at 4 to 24 h, a subsequent attenuating phase, followed by a late persistent phase that lasted for months. The downregulation of GLT1 occurred at a time when hyperalgesia transitioned into the persistent phase. In the rostral ventromedial medulla, pharmacological block with dihydrokainic acid and RNAi of GLT1 and KBBP increased nociception and overexpression of GLT1 reversed persistent hyperalgesia. Further, the initial upregulation of GLT1 and KBBP was blocked by local anesthetic block, and pretreatment with dihydrokainic acid facilitated the development of hyperalgesia.
These results suggest that the initial increased GLT1 activity depends on injury input and serves to dampen the development of hyperalgesia. However, later downregulation of GLT1 fosters the net descending facilitation as injury persists, leading to the emergence of persistent pain.
谷氨酸转运体 1（GLT1）在大脑中的谷氨酸稳态中起着重要作用。尽管 GLT1 活性的改变与持续性疼痛有关，但这些变化的意义尚不清楚。本研究聚焦于痛觉调制的关键部位——延髓头端腹内侧区，观察佐剂诱导的大鼠后爪炎症后 GLT1 及其相关转录因子κB 基序结合磷蛋白（KBBP）的表达和功能变化。
炎症后，GLT1 和 KBBP 表现出早期上调，随后逐渐下调，并持续观察 8 周。GLT1 的硝化作用在炎症后 30 分钟减少，8 周时增加，提示转运体活性先增加后减少。机械性痛觉过敏和爪肿胀表现出初始发展阶段，在 4 至 24 小时达到痛觉过敏高峰，随后是衰减阶段，随后是持续数月的晚期持续阶段。GLT1 的下调发生在痛觉过敏向持续性转变的时期。在延髓头端腹内侧区，用二氢酮酸进行药理学阻断以及 GLT1 和 KBBP 的 RNAi 可增加痛觉传入，过表达 GLT1 可逆转持续性痛觉过敏。此外，局部麻醉阻断了 GLT1 和 KBBP 的初始上调，二氢酮酸预处理促进了痛觉过敏的发展。
这些结果表明，初始增加的 GLT1 活性依赖于损伤输入，有助于抑制痛觉过敏的发展。然而，GLT1 的后期下调促进了损伤持续存在时的下行促进作用，导致持续性疼痛的出现。
