Department of Physiology, Wakayama Medical University, Kimiidera 811-1, Wakayama City 641-8509, Japan.
Radioisotope Laboratory Center, Wakayama Medical University, Kimiidera 811-1, Wakayama City 641-8509, Japan.
Brain Res. 2023 Sep 15;1815:148465. doi: 10.1016/j.brainres.2023.148465. Epub 2023 Jun 16.
Repeated exposure to psychophysical stress often causes an increase in sensitivity and response to pain. This phenomenon is commonly called stress-induced hyperalgesia (SIH). Although psychophysical stress is a well-known risk factor for numerous chronic pain syndromes, the neural mechanism underlying SIH has not yet been elucidated. The rostral ventromedial medulla (RVM) is a key output element of the descending pain modulation system. Descending signals from the RVM have a major impact on spinal nociceptive neurotransmission. In the present study, to clarify changes in the descending pain modulatory system in rats with SIH, we examined the expression of Mu opioid receptor (MOR) mRNA, MeCP2 and global DNA methylation in the RVM after repeated restraint stress for 3 weeks. Additionally, we microinjected neurotoxin dermorphin-SAP into the RVM. The repeated restraint stress for 3 weeks induced mechanical hypersensitivity in the hind paw, a significant increase in the expression of MOR mRNA and MeCP2, and a significant decrease in global DNA methylation in the RVM. The MeCP2 binding to MOR gene promoter in the RVM was significantly decreased in rats with repeated restraint stress. Furthermore, microinjection of dermorphin-SAP into the RVM prevented the mechanical hypersensitivity induced by repeated restraint stress. Although, because of the lack of specific antibody to MOR, we could not show a quantitative analysis in the number of MOR-expressing neurons after the microinjection, these results suggest that MOR-expressing neurons in the RVM induce SIH after repeated restraint stress.
反复暴露于心理生理性应激通常会导致对疼痛的敏感性和反应性增加。这种现象通常称为应激诱导性痛觉过敏（SIH）。尽管心理生理性应激是许多慢性疼痛综合征的已知危险因素，但 SIH 的神经机制尚未阐明。延髓头端腹内侧区（RVM）是下行疼痛调节系统的关键输出元件。来自 RVM 的下行信号对脊髓伤害性神经传递有重大影响。在本研究中，为了阐明 SIH 大鼠下行疼痛调制系统的变化，我们在重复束缚应激 3 周后检查了 RVM 中 μ 阿片受体（MOR）mRNA、MeCP2 和全基因组 DNA 甲基化的表达。此外，我们将神经毒素 Dermorphin-SAP 微注射到 RVM 中。重复束缚应激 3 周导致后爪机械性痛觉过敏，MOR mRNA 和 MeCP2 的表达显著增加，RVM 中的全基因组 DNA 甲基化显著降低。重复束缚应激大鼠 RVM 中 MeCP2 与 MOR 基因启动子的结合显著减少。此外，RVM 中的 Dermorphin-SAP 微注射可预防重复束缚应激引起的机械性痛觉过敏。尽管由于缺乏 MOR 的特异性抗体，我们无法在微注射后显示 MOR 表达神经元的数量进行定量分析，但这些结果表明 RVM 中的 MOR 表达神经元在重复束缚应激后会引起 SIH。
