Alleviating Bone Cancer-induced Mechanical Hypersensitivity by Inhibiting Neuronal Activity in the Anterior Cingulate Cortex
Alleviating Bone Cancer-induced Mechanical Hypersensitivity by Inhibiting Neuronal Activity in the Anterior Cingulate Cortex
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DOI：
10.1097/aln.0000000000001237
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发表时间：
2016-10-01
期刊：
影响因子：
8.8
通讯作者：
Hsu, Kuei-Sen
中科院分区：
文献类型：
--
作者：
Chiou, Chiuan-Shiou;Chen, Chien-Chung;Hsu, Kuei-Sen
背景：前扣带皮层（ACC）是一个在疼痛感知和调节过程中起关键作用的大脑区域。虽然许多证据表明慢性疼痛状态下ACC的活动增加，但对于是否可以通过抑制ACC神经元活动来减轻疼痛知之甚少。方法：作者采用药理学、化学遗传学和光遗传学方法，结合病毒追踪技术，在胫骨内植入溶骨纤维肉瘤细胞的骨癌机械过敏小鼠模型中解决了这一问题。结果：双侧acc内显微注射。-氨基丁酸受体A型受体激动剂muscimol降低荷瘤小鼠的机械超敏反应（n = 10）。通过腺病毒介导表达工程G（i/o）偶联的人M4 （hM4Di）受体，我们观察到G（i/o）偶联的人M4受体与氯氮平- n -氧化物的激活降低了肿瘤小鼠ACC神经元的活性和机械超敏反应（n = 11）。此外，用盐视紫红质单侧光遗传沉默ACC兴奋性神经元可显著降低肿瘤小鼠的机械超敏反应（n = 4 ~ 9），相反，用通道视紫红质-2光遗传激活这些神经元足以引起假手术小鼠的机械超敏反应（n = 5 ~ 9）。此外，我们发现ACC中的兴奋性神经元通过背皮质脊髓束向对侧腰椎背角发送直接下降的投射。结论：本研究结果表明，ACC神经元活动增强有助于维持骨癌诱导的机械超敏反应，并提示ACC可能作为治疗骨癌疼痛的潜在治疗靶点。
Background: The anterior cingulate cortex (ACC) is a brain region that has been critically implicated in the processing of pain perception and modulation. While much evidence has pointed to an increased activity of the ACC under chronic pain states, less is known about whether pain can be alleviated by inhibiting ACC neuronal activity.Methods: The authors used pharmacologic, chemogenetic, and optogenetic approaches in concert with viral tracing technique to address this issue in a mouse model of bone cancer-induced mechanical hypersensitivity by intratibia implantation of osteolytic fibrosarcoma cells.Results: Bilateral intra-ACC microinjections of.-aminobutyric acid receptor type A receptor agonist muscimol decreased mechanical hypersensitivity in tumor-bearing mice (n = 10). Using adenoviral-mediated expression of engineered G(i/o)-coupled human M4 (hM4Di) receptors, we observed that activation of G(i/o)-coupled human M4 receptors with clozapine-N-oxide reduced ACC neuronal activity and mechanical hypersensitivity in tumor-bearing mice (n = 11). In addition, unilateral optogenetic silencing of ACC excitatory neurons with halorhodopsin significantly decreased mechanical hypersensitivity in tumor-bearing mice (n = 4 to 9), and conversely, optogenetic activation of these neurons with channelrhodopsin-2 was sufficient to provoke mechanical hypersensitivity in sham-operated mice (n = 5 to 9). Furthermore, we found that excitatory neurons in the ACC send direct descending projections to the contralateral dorsal horn of the lumbar spinal cord via the dorsal corticospinal tract.Conclusions: The findings of this study indicate that enhanced neuronal activity in the ACC contributes to maintain bone cancer-induced mechanical hypersensitivity and suggest that the ACC may serve as a potential therapeutic target for treating bone cancer pain.