Pharmacological ablation of rostral ventromedial medulla (RVM) mu opioid receptor-expressing cells before peripheral nerve injury prevents the development of neuropathic pain. However, whether these neurons are required for the expression of established neuropathic pain is not known. Male Oprm1Cre heterozygous (MORCre) or wild-type (MORWT) mice received AAV8-hSyn-DIO-hM4D(Gi)-mCherry in the RVM. After partial sciatic nerve ligation (PSNL), we evaluated pain behaviors and descending control of nociception in response to acute or sustained chemogenetic inhibition of RVM-MOR cells expressing hM4D(Gi). A single systemic administration of hM4D(Gi) agonist clozapine-N-oxide (CNO) reversibly inhibited hind paw tactile allodynia and produced conditioned place preference only in MORCre mice with PSNL. Intrathecal CNO also reversibly inhibited PSNL-induced hind paw allodynia, suggesting that the spinal projections from these RVM-MOR cells are critical for manifestation of pain behaviors. Consistent with enhanced descending facilitation from RVM-MOR cells, MORCre-hM4D(Gi) mice with PSNL showed diminished descending control of nociception that was restored by systemic CNO. Sustained CNO in drinking water before PSNL prevented expression of chronic pain without affecting acute surgical pain; however, relief of chronic pain required sustained CNO treatment. Thus, in male mice, activity of spinally projecting RVM-MOR cells is required (1) for expression and manifestation of both sensory and affective dimensions of established neuropathic pain and (2) to promote descending facilitation that overcomes apparently intact descending inhibition to maintain chronic pain. Enhanced descending facilitation likely regulates the output signal from the spinal cord to the brain to shape the pain experience and may provide a mechanism for nonopioid management of pain.

中文翻译：

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从喙腹内侧延髓 mu 阿片受体表达神经元的下行促进对于维持慢性神经性疼痛的感觉和情感维度是必要的。


在周围神经损伤前对喙腹内侧延髓 （RVM） μ 阿片受体表达细胞进行药物消融可防止神经性疼痛的发展。然而，这些神经元是否是已建立的神经性疼痛表达所必需的尚不清楚。雄性 Oprm1Cre 杂合子 （MORCre） 或野生型 （MORWT） 小鼠在 RVM 中接受 AAV8-hSyn-DIO-hM4D（Gi）-mCherry。部分坐骨神经结扎 （PSNL） 后，我们评估了表达 hM4D （Gi） 的 RVM-MOR 细胞急性或持续化疗遗传学抑制的疼痛行为和伤害感受的下降控制。hM4D（Gi） 激动剂氯氮平-N-氧化物 （CNO） 的单次全身给药可逆地抑制后爪触觉异常性疼痛，并且仅在具有 PSNL 的 MORCre 小鼠中产生条件性位置偏好。鞘内 CNO 还可逆地抑制了 PSNL 诱导的后爪异常性疼痛，表明这些 RVM-MOR 细胞的脊柱投射对于疼痛行为的表现至关重要。与 RVM-MOR 细胞增强的下降易化性一致，具有 PSNL 的 MORCre-hM4D （Gi） 小鼠表现出对全身性 CNO 恢复的伤害感受的下降控制减弱。PSNL 前饮用水中的持续 CNO 可防止慢性疼痛的表达而不影响急性手术疼痛;然而，缓解慢性疼痛需要持续的 CNO 治疗。因此，在雄性小鼠中，需要脊髓突出的 RVM-MOR 细胞的活性 （1） 表达和表现已建立的神经性疼痛的感觉和情感维度，以及 （2） 促进克服明显完整的下降抑制的下降便利化以维持慢性疼痛。 增强的下降易化性可能调节从脊髓到大脑的输出信号以塑造疼痛体验，并可能为非阿片类药物的疼痛管理提供一种机制。