μ-Opioid Receptor Activation at the Dorsal Reticular Nucleus Shifts Diffuse Noxious Inhibitory Controls to Hyperalgesia in Chronic Joint Pain in Male Rats.

IF 9.1 1区医学 Q1 ANESTHESIOLOGY Anesthesiology Pub Date : 2024-06-01 DOI:10.1097/ALN.0000000000004956

Raquel Pereira-Silva, Armando Teixeira-Pinto, Fani L Neto, Isabel Martins

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Abstract

Background: The dorsal reticular nucleus is a pain facilitatory area involved in diffuse noxious inhibitory control (DNIC) through opioidergic mechanisms that are poorly understood. The hypothesis was that signaling of μ-opioid receptors is altered in this area with prolonged chronic inflammatory pain and that this accounts for the loss of DNICs occurring in this condition.

Methods: Monoarthritis was induced in male Wistar rats (n = 5 to 9/group) by tibiotarsal injection of complete Freund's adjuvant. The immunolabeling of µ-opioid receptors and the phosphorylated forms of µ-opioid receptors and cAMP response element binding protein was quantified. Pharmacologic manipulation of μ-opioid receptors at the dorsal reticular nucleus was assessed in DNIC using the Randall-Selitto test.

Results: At 42 days of monoarthritis, μ-opioid receptor labeling decreased at the dorsal reticular nucleus, while its phosphorylated form and the phosphorylated cAMP response element binding protein increased. [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin acetate (DAMGO) enhanced DNIC analgesia in normal animals (means ± SD: pre-DNIC: 126.9 ± 7.0 g; DNIC - DAMGO: 147.5 ± 8.0 g vs. DNIC + DAMGO: 198.1 ± 19.3 g; P < 0.001), whereas it produced hyperalgesia in monoarthritis (pre-DNIC: 67.8 ± 7.5 g; DNIC - DAMGO: 70.6 ± 7.7 g vs. DNIC + DAMGO: 32.2 ± 2.6 g; P < 0.001). An ultra-low dose of naloxone, which prevents the excitatory signaling of the μ-opioid receptor, restored DNIC analgesia in monoarthritis (DNIC - naloxone: 60.0 ± 6.1 g vs. DNIC + naloxone: 98.0 ± 13.5 g; P < 0.001), compared to saline (DNIC - saline: 62.5 ± 5.2 g vs. DNIC + saline: 64.2 ± 3.8 g). When injected before DAMGO, it restored DNIC analgesia and decreased the phosphorylated cAMP response element binding protein in monoarthritis.

Conclusions: The dorsal reticular nucleus is likely involved in a facilitatory pathway responsible for DNIC hyperalgesia. The shift of μ-opioid receptor signaling to excitatory in this pathway likely accounts for the loss of DNIC analgesia in monoarthritis.

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激活背侧网状核的μ-阿片受体可使雄性大鼠慢性关节痛的弥漫性毒性抑制控制转向痛觉亢进。

背景：背侧网状核是一个疼痛促进区，它通过阿片受体机制参与弥漫性疼痛抑制控制（DNIC），但对其机制还不甚了解。我们假设，在长期慢性炎症性疼痛时，该区域的μ-阿片受体信号会发生改变，这也是这种情况下DNIC丧失的原因：方法：雄性 Wistar 大鼠（n=5-9/组）通过胫骨注射完全弗氏佐剂诱发单关节炎。我们对µ-阿片受体以及µ-阿片受体和cAMP反应元件结合蛋白的磷酸化形式进行了免疫标记定量。通过Randall-Selitto试验，对DNIC背侧网状核μ-阿片受体的药理作用进行了评估：结果：在单关节炎42天时，背侧网状核的μ-阿片受体标记减少，而其磷酸化形式和磷酸化的cAMP反应元件结合蛋白增加。D-ALA2,N-ME-PHE4,GLY5-OL)-脑啡肽醋酸酯（DAMGO）增强了正常动物的 DNIC 镇痛效果（[平均值 ± SD]：DNIC 前：126.9 ± 7.0g；DNIC - DAMGO：147.5 ± 8.0g vs. DNIC + DAMGO：198.1 ± 19.3g，p < 0.001），而在单关节炎中则会产生痛觉减退（DNIC 前：67.8 ± 7.5g；DNIC - DAMGO：70.6 ± 7.7g vs. DNIC + DAMGO：32.2 ± 2.6g，p < 0.001）。超低剂量的纳洛酮能阻止μ-阿片受体的兴奋信号传导，与生理盐水（DNIC - 生理盐水：62.5 ± 5.2g vs. DNIC + 生理盐水：64.2 ± 3.8g）相比，它能恢复单关节炎患者的 DNIC 镇痛效果（DNIC - 纳洛酮：60.0 ± 6.1g vs. DNIC + 纳洛酮：98.0 ± 13.5g，p < 0.001）。在注射 DAMGO 之前，DAMGO 可恢复 DNIC 镇痛效果，并降低单关节炎患者磷酸化 cAMP 反应元件结合蛋白的含量：结论：背网状核可能参与了导致 DNIC 痛觉减退的促进途径。该通路中的μ-阿片受体信号转导为兴奋性信号，这可能是单关节炎患者DNIC镇痛丧失的原因。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Anesthesiology 医学-麻醉学

CiteScore

10.40

自引率

5.70%

发文量

542

审稿时长

3-6 weeks

期刊介绍： With its establishment in 1940, Anesthesiology has emerged as a prominent leader in the field of anesthesiology, encompassing perioperative, critical care, and pain medicine. As the esteemed journal of the American Society of Anesthesiologists, Anesthesiology operates independently with full editorial freedom. Its distinguished Editorial Board, comprising renowned professionals from across the globe, drives the advancement of the specialty by presenting innovative research through immediate open access to select articles and granting free access to all published articles after a six-month period. Furthermore, Anesthesiology actively promotes groundbreaking studies through an influential press release program. The journal's unwavering commitment lies in the dissemination of exemplary work that enhances clinical practice and revolutionizes the practice of medicine within our discipline.