Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 S. Orange Ave., MSB, E-661, Newark, NJ, 07103, USA.
Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China.
Neurotherapeutics. 2019 Apr;16(2):491-504. doi: 10.1007/s13311-018-00689-x.
Peripheral nerve injury downregulates the expression of the μ-opioid receptor (MOR) and voltage-gated potassium channel subunit Kv1.2 by increasing their DNA methylation in the dorsal root ganglion (DRG). Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) causes DNA demethylation. Given that DRG MOR and Kv1.2 downregulation contribute to neuropathic pain genesis, this study investigated the effect of DRG TET1 overexpression on neuropathic pain. Overexpression of TET1 in the DRG through microinjection of herpes simplex virus expressing full-length TET1 mRNA into the injured rat DRG significantly alleviated the fifth lumbar spinal nerve ligation (SNL)-induced pain hypersensitivities during the development and maintenance periods, without altering acute pain or locomotor function. This microinjection also restored morphine analgesia and attenuated morphine analgesic tolerance development after SNL. Mechanistically, TET1 microinjection rescued the expression of MOR and Kv1.2 by reducing the level of 5-methylcytosine and increasing the level of 5-hydroxymethylcytosine in the promoter and 5' untranslated regions of the Oprml1 gene (encoding MOR) and in the promoter region of the Kcna2 gene (encoding Kv1.2) in the DRG ipsilateral to SNL. These findings suggest that DRG TET1 overexpression mitigated neuropathic pain likely through rescue of MOR and Kv1.2 expression in the ipsilateral DRG. Virus-mediated DRG delivery of TET1 may open a new avenue for neuropathic pain management.
周围神经损伤通过增加背根神经节（DRG）中μ-阿片受体（MOR）和电压门控钾通道亚单位 Kv1.2 的 DNA 甲基化来下调其表达。Ten-eleven 易位甲基胞嘧啶双加氧酶 1（TET1）引起 DNA 去甲基化。鉴于 DRG MOR 和 Kv1.2 的下调有助于神经性疼痛的发生，本研究探讨了 DRG TET1 过表达对神经性疼痛的影响。通过将全长 TET1 mRNA 的单纯疱疹病毒微注射到损伤的大鼠 DRG 中来过表达 DRG TET1，可显著缓解第 5 腰椎脊神经结扎（SNL）诱导的疼痛敏化在发展和维持期间，而不改变急性疼痛或运动功能。这种微注射还恢复了吗啡镇痛，并减轻了 SNL 后吗啡镇痛耐受的发展。从机制上讲，TET1 微注射通过降低 Oprml1 基因（编码 MOR）启动子和 5'非翻译区以及 Kcna2 基因（编码 Kv1.2）启动子区域中 5-甲基胞嘧啶的水平，同时增加 5-羟甲基胞嘧啶的水平，挽救了 MOR 和 Kv1.2 的表达同侧 SNL 的 DRG。这些发现表明，DRG TET1 过表达通过挽救同侧 DRG 中的 MOR 和 Kv1.2 表达来减轻神经性疼痛。病毒介导的 DRG 中 TET1 的传递可能为神经性疼痛管理开辟新途径。
