Anesthesiology and Clinical Physiology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Pharmacology, Nippon Medical School, Tokyo, Japan.
Mol Pain. 2020 Jan-Dec;16:1744806920904462. doi: 10.1177/1744806920904462.
Transcriptional changes in primary sensory neurons are involved in initiation and maintenance of neuropathic pain. However, the transcription factors in primary sensory neurons responsible for neuropathic pain are not fully understood. Dorsal Root Ganglia Homeobox (DRGX) is a paired-like homeodomain transcription factor necessary for the development of nociceptive primary sensory neurons during the early postnatal period. However, roles for DRGX after development are largely unknown. Here, we report that DRGX downregulation in primary sensory neurons as a result of post-developmental nerve injury contributes to neuropathic pain in rats. DRGX expression was decreased in nuclei of small and medium primary sensory neurons after spinal nerve ligation. DRGX downregulation by transduction of a short hairpin RNA with an adeno-associated viral vector induced mechanical allodynia and thermal hyperalgesia. In contrast, DRGX overexpression in primary sensory neurons suppressed neuropathic pain. DRGX regulated matrix metalloproteinase-9 (MMP-9) and prostaglandin E receptor 2 mRNA expression in the DRG. MMP-9 inhibitor attenuated DRGX downregulation-induced pain. These results suggest that DRGX downregulation after development contributes to neuropathic pain through transcriptional modulation of pain-related genes in primary sensory neurons.
初级感觉神经元中的转录变化参与了神经性疼痛的起始和维持。然而，负责神经性疼痛的初级感觉神经元中的转录因子尚未完全阐明。背根神经节同源盒 (DRGX) 是一种配对样同源结构域转录因子，对于出生后早期伤害性初级感觉神经元的发育是必需的。然而，DRGX 在发育后的作用在很大程度上是未知的。在这里，我们报告说，初级感觉神经元中 DRGX 的下调是由于发育后的神经损伤导致大鼠神经性疼痛的原因。脊髓神经结扎后，小和中初级感觉神经元的细胞核中 DRGX 表达减少。腺相关病毒载体转导短发夹 RNA 下调 DRGX 会引起机械性痛觉过敏和热痛觉过敏。相比之下，初级感觉神经元中的 DRGX 过表达会抑制神经性疼痛。DRGX 调节 DRG 中基质金属蛋白酶-9 (MMP-9) 和前列腺素 E 受体 2 mRNA 的表达。MMP-9 抑制剂可减弱 DRGX 下调诱导的疼痛。这些结果表明，发育后 DRGX 的下调通过初级感觉神经元中与疼痛相关基因的转录调节导致神经性疼痛。
