Focal mu-opioid receptor activation promotes neuroinflammation and microglial activation in the mesocorticolimbic system: Alterations induced by inflammatory pain,Glia

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Focal mu-opioid receptor activation promotes neuroinflammation and microglial activation in the mesocorticolimbic system: Alterations induced by inflammatory pain
Glia ( IF 5.4 ) Pub Date : 2023-04-05 , DOI: 10.1002/glia.24374
Javier Cuitavi _{1,

2} , Paula Andrés-Herrera _{1,

2} , David Meseguer ₁ , Yolanda Campos-Jurado ₁ , Jesús D Lorente ₁ , Hannah Caruana ₁ , Lucía Hipólito _{1,

2}

Affiliation

Microglia participates in the modulation of pain signaling. The activation of microglia is suggested to play an important role in affective disorders that are related to a dysfunction of the mesocorticolimbic system (MCLS) and are commonly associated with chronic pain. Moreover, there is evidence that mu-opioid receptors (MORs), expressed in the MCLS, are involved in neuroinflammatory events, although the way by which they do it remains to be elucidated. In this study, we propose that MOR pharmacological activation within the MCLS activates and triggers the local release of proinflammatory cytokines and this pattern of activation is impacted by the presence of systemic inflammatory pain. To test this hypothesis, we used in vivo microdialysis coupled with flow cytometry to measure cytokines release in the nucleus accumbens and immunofluorescence of IBA1 in areas of the MCLS on a rat model of inflammatory pain. Interestingly, the treatment with DAMGO, a MOR agonist locally in the nucleus accumbens, triggered the release of the IL1α, IL1β, and IL6 proinflammatory cytokines. Furthermore, MOR pharmacological activation in the ventral tegmental area (VTA) modified the levels of IBA1-positive cells in the VTA, prefrontal cortex, the nucleus accumbens and the amygdala in a dose-dependent way, without impacting mechanical nociception. Additionally, MOR blockade in the VTA prevents DAMGO-induced effects. Finally, we observed that systemic inflammatory pain altered the IBA1 immunostaining derived from MOR activation in the MSCLS. Altogether, our results indicate that the microglia–MOR relationship could be pivotal to unravel some inflammatory pain-induced comorbidities related to MCLS dysfunction.

中文翻译：

局部μ阿片受体激活促进中皮质边缘系统中的神经炎症和小胶质细胞激活：炎性疼痛引起的改变

小胶质细胞参与疼痛信号的调节。小胶质细胞的激活被认为在与中皮质边缘系统（MCLS）功能障碍相关的情感障碍中发挥重要作用，并且通常与慢性疼痛相关。此外，有证据表明，在 MCLS 中表达的 mu-阿片受体 (MOR) 参与神经炎症事件，尽管它们的作用方式仍有待阐明。在这项研究中，我们提出 MCLS 内的 MOR 药理激活会激活并触发促炎细胞因子的局部释放，并且这种激活模式受到全身炎症疼痛的影响。为了检验这一假设，我们使用体内微透析结合流式细胞术来测量炎症性疼痛大鼠模型中伏隔核中细胞因子的释放以及 MCLS 区域中 IBA1 的免疫荧光。有趣的是，用 DAMGO（一种伏隔核局部 MOR 激动剂）治疗，触发了 IL1α、IL1β 和 IL6 促炎细胞因子的释放。此外，腹侧被盖区 (VTA) 的 MOR 药理学激活以剂量依赖性方式改变了 VTA、前额皮质、伏核和杏仁核中 IBA1 阳性细胞的水平，而不影响机械伤害感受。此外，VTA 中的 MOR 阻断可防止 DAMGO 引起的效应。最后，我们观察到全身炎症疼痛改变了 MSCLS 中 MOR 激活产生的 IBA1 免疫染色。总而言之，我们的结果表明，小胶质细胞与 MOR 的关系可能对于解决一些与 MCLS 功能障碍相关的炎症性疼痛引起的合并症至关重要。

更新日期：2023-04-05

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