Altered Signaling in the Descending Pain-modulatory System after Short-Term Infusion of the μ-Opioid Agonist Remifentanil
Altered Signaling in the Descending Pain-modulatory System after Short-Term Infusion of the μ-Opioid Agonist Remifentanil
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DOI：
10.1523/jneurosci.2496-17.2018
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发表时间：
2018-03-07
影响因子：
5.3
通讯作者：
Buechel, Christian
中科院分区：
文献类型：
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作者：
Sprenger, Christian;Eichler, Iris-Carola;Buechel, Christian
mu-阿片受体激动剂广泛用于当代疼痛治疗，但突然暂停阿片类药物，即使是在短期输注后，也会矛盾地增加对有害刺激的敏感性，例如，在应用速效mu-阿片受体激动剂瑞芬太尼后就有报道称这种现象。为了研究停止使用瑞芬太尼对人类中枢神经系统疼痛处理影响的潜在机制，我们使用 fMRI 分析了短期输注瑞芬太尼（30 分钟 0.1 μg/kg 体重/分钟）之前和之后的神经元对热刺激的反应，并与对照组相比，使用 fMRI 分析了未接受药物治疗的男性志愿者的大脑、脑干和脊髓。瑞芬太尼混悬液后，我们观察到疼痛编码以及下行疼痛调节系统关键区域（如导水管周围灰质、楔状核和头端腹内侧延髓）的热痛阈值降低，神经元反应增加。此外，药物悬浮后，与脊柱疼痛相关的多体素活动模式显示出阿片类药物特异性的变化。重要的是，瑞芬太尼混悬液增加了楔状核和吻侧前扣带皮层之间的功能耦合，并且吻侧前扣带皮层和楔形核之间的耦合强度与阿片类药物混悬后的个体痛阈呈负相关。这些发现表明，在短期输注μ阿片受体激动剂瑞芬太尼后，下行疼痛调节系统中的信号传导发生了根本性改变，并且这些变化与对疼痛的行为敏感性直接相关。
mu-Opioid receptor agonists are widely used within the contemporary treatment of pain, but abrupt opioid suspension, even after short-term infusion, can paradoxically increase the sensitivity to noxious stimuli, a phenomenon that has been, for example, reported after application of the fast-acting mu-opioid receptor agonist remifentanil. To investigate the mechanisms underlying the effects of discontinuation of remifentanil application on pain processing in the human CNS, we analyzed neuronal responses to thermal stimuli before and after a short-term infusion of remifentanil (30 min 0.1 mu g/kg body weight/min) compared with control in the brain, brainstem, and spinal cord in drug-naive male volunteers using fMRI. Subsequent to remifentanil suspension, we observed reduced heat pain thresholds and increased neuronal responses in pain-encoding as well as in key regions of the descending pain-modulatory system, such as the periaqueductal gray matter, the nucleus cuneiformis, and the rostral ventromedial medulla. Moreover, the spinal pain-related multivoxel activity pattern showed an opioid-specific change after drug suspension. Importantly, remifentanil suspension increased the functional coupling between the nucleus cuneiformis and the rostral anterior cingulate cortex, and the coupling strength between the rostral anterior cingulate cortex and the nucleus cuneiformis correlated negatively with the individual pain threshold after opioid suspension. These findings demonstrate that, already subsequent to a short-term infusion of the mu-opioid receptor agonist remifentanil, signaling in the descending pain-modulatory system is fundamentally altered and that these changes are directly related to the behavioral sensitivity to pain.