Department of Anesthesiology, Tianjin Research Institute of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.
Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, China.
Mol Pain. 2023 Jan-Dec;19:17448069231178271. doi: 10.1177/17448069231178271.
Fentanyl and its analogs are extensively used for pain relief. However, their paradoxically pronociceptive effects often lead to increased opioids consumption and risk of chronic pain. Compared to other synthetic opioids, remifentanil has been strongly linked to acute opioid hyperalgesia after exposure [remifentanil-induced hyperalgesia (RIH)]. The epigenetic regulation of microRNAs (miRNAs) on targeted mRNAs has emerged as an important pathogenesis in pain. The current research aimed at exploring the significance and contributions of miR-134-5p to the development of RIH. Both the antinociceptive and pronociceptive effects of two commonly used opioids were assessed, and miRNA expression profiles in the spinal dorsal horn (SDH) of mice acutely exposed to remifentanil and remifentanil equianalgesic dose (RED) sufentanil were screened. Next, the candidate miRNA level, cellular distribution, and function were examined by qPCR, fluorescent in situ hybridization (FISH) and Argonaute-2 immunoprecipitation. Furthermore, bioinformatics analysis, luciferase assays, miRNA overexpression, behavioral tests, golgi staining, electron microscopy, whole-cell patch-clamp recording, and immunoblotting were employed to investigate the potential targets and mechanisms underlying RIH. Remifentanil induced significant pronociceptive effects and a distinct miRNA-profile from sufentanil when compared to saline controls. Among top 30 differentially expressed miRNAs spectrum, spinal miR-134-5p was dramatically downregulated in RIH mice but remained comparative in mice subjected to sufentanil. Moreover, Glutamate Receptor Ionotropic Kainate 3 (Grik3) was a target of miR-134-5p. The overexpression of miR-134-5p attenuated the hyperalgesic phenotype, excessive dendritic spine remodeling, excitatory synaptic structural plasticity, and Kainate receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in SDH resulting from remifentanil exposure. Besides, intrathecal injection of selective KA-R antagonist was able to reverse the GRIK3 membrane trafficking and relieved RIH. The miR-134-5p contributes to remifentanil-induced pronociceptive features via directly targeting Grik3 to modulate dendritic spine morphology and synaptic plasticity in spinal neurons.
芬太尼及其类似物被广泛用于缓解疼痛。然而，它们的矛盾性促痛作用常常导致阿片类药物消耗增加和慢性疼痛的风险。与其他合成阿片类药物相比，瑞芬太尼与接触后的急性阿片类药物超敏反应（RIH）强烈相关。miRNAs（miRNA）对靶向 mRNAs 的表观遗传调控已成为疼痛发病机制的一个重要方面。目前的研究旨在探讨 miR-134-5p 对 RIH 发展的意义和贡献。评估了两种常用阿片类药物的抗伤害和促伤害作用，并筛选了急性暴露于瑞芬太尼和瑞芬太尼等效剂量（RED）舒芬太尼的小鼠脊髓背角（SDH）中的 miRNA 表达谱。接下来，通过 qPCR、荧光原位杂交（FISH）和 Argonaute-2 免疫沉淀检查候选 miRNA 水平、细胞分布和功能。此外，还采用生物信息学分析、荧光素酶测定、miRNA 过表达、行为测试、高尔基染色、电子显微镜、全细胞膜片钳记录和免疫印迹法，研究 RIH 的潜在靶点和机制。与生理盐水对照相比，瑞芬太尼诱导明显的促伤害作用和独特的 miRNA 谱，而舒芬太尼则无此作用。在差异表达 miRNA 谱的前 30 种中，RIH 小鼠脊髓中的 miR-134-5p 明显下调，但在舒芬太尼处理的小鼠中则相对不变。此外，谷氨酸受体离子型 kainate 3（Grik3）是 miR-134-5p 的靶点。miR-134-5p 的过表达减轻了瑞芬太尼暴露引起的 SDH 中的痛觉过敏表型、过度树突棘重塑、兴奋性突触结构可塑性和 kainate 受体介导的微小兴奋性突触后电流（mEPSCs）。此外，鞘内注射选择性 KA-R 拮抗剂能够逆转 GRIK3 膜转运并缓解 RIH。miR-134-5p 通过直接靶向 Grik3 调节脊髓神经元中的树突棘形态和突触可塑性，从而促进瑞芬太尼诱导的促伤害特征。
