Activation of the Intrinsic Pain Inhibitory Circuit from the Midcingulate Cg2 to Zona Incerta Alleviates Neuropathic Pain
Activation of the Intrinsic Pain Inhibitory Circuit from the Midcingulate Cg2 to Zona Incerta Alleviates Neuropathic Pain
复制标题
激活从中扣带回 Cg2 到不确定带的内在疼痛抑制电路可减轻神经性疼痛
DOI：
10.1523/jneurosci.1683-19.2019
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发表时间：
2019-11-13
影响因子：
5.3
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Hu, Ting-Ting;Wang, Ran-Ran;Chen, Zhong
神经病理性疼痛是最常见和最臭名昭著的神经系统疾病之一。神经损伤后大脑结构的变化及其对神经病理性疼痛的影响还不清楚。本研究发现，雄性小鼠中扣带回皮质2区（MCC Cg2Glu）的大部分多巴胺能神经元受到疼痛刺激的抑制。光遗传学操作显示，这些神经元紧张性参与多模态伤害性感受的抑制性调制。我们进一步确定了向三叉神经节GABA能神经元的投射（ZIGABA）介导的疼痛抑制作用。然而，MCC Cg2Glu在神经损伤后变得低活性。虽然MCC Cg2Glu至ZIGABA回路的短暂激活能够缓解与自发持续疼痛相关的厌恶，但需要连续激活该回路以缓解神经性异常性疼痛。相反，MCC 1区的多巴胺能神经元在痛觉调制中起相反的作用。它们在神经损伤后变得过度活跃，只有连续抑制它们的活动才能减轻异常性疼痛。这些结果表明，MCC Cg2Glu构成了一个组成部分的内在疼痛抑制回路和他们的低活性的神经病理性疼痛的基础。我们建议，选择性和持续激活的MCC Cg2Glu到ZIGABA电路可能作为一个潜在的治疗策略，这种疾病。中扣带回皮质2区（MCC Cg2Glu）的谷氨酸能神经元通过投射到齿状回的GABA能神经元而紧张性地参与内源性疼痛抑制。它们在神经损伤后活动减退。回路的选择性激活补偿其镇痛强度的降低并缓解神经性疼痛。因此，MCC Cg 2Glu和相关的镇痛回路可能作为神经性疼痛的治疗靶点。相比之下，MCC Cg1Glu在疼痛调制中具有相反的作用，并且在神经损伤后变得过度活跃。本研究为神经病理性疼痛与内源性疼痛调节系统功能障碍有关的观点提供了新的证据，为神经病理性疼痛的治疗提供了新的视角。
Neuropathic pain is one of the most common and notorious neurological diseases. The changes in cerebral structures after nerve injury and the corresponding contributions to neuropathic pain are not well understood. Here we found that the majority of glutamatergic neurons in the area 2 of midcingulate cortex (MCC Cg2Glu) were inhibited by painful stimulation in male mice. Optogenetic manipulation revealed that these neurons were tonically involved in the inhibitory modulation of multimodal nociception. We further identified the projections to GABAergic neurons in the zona incerta (ZIGABA) mediated the pain inhibitory role. However, MCC Cg2Glu became hypoactive after nerve injury. Although a brief activation of the MCC Cg2Glu to ZIGABA circuit was able to relieve the aversiveness associated with spontaneous ongoing pain, consecutive activation of the circuit was required to alleviate neuropathic allodynia. In contrast, glutamatergic neurons in the area 1 of MCC played opposite roles in pain modulation. They became hyperactive after nerve injury and only consecutive inhibition of their activity relieved allodynia. These results demonstrate that MCC Cg2Glu constitute a component of intrinsic pain inhibitory circuitry and their hypoactivity underlies neuropathic pain. We propose that selective and persistent activation of the MCC Cg2Glu to ZIGABA circuit may serve as a potential therapeutic strategy for this disease. SIGNIFICANCE STATEMENT Glutamatergic neurons in the area 2 of midcingulate cortex (MCC Cg2Glu) are tonically involved in the intrinsic pain inhibition via projecting to GABAergic neurons in the zona incerta. They are hypoactive after nerve injury. Selective activation of the circuit compensates the reduction of its analgesic strength and relieves neuropathic pain. Therefore, MCC Cg2Glu and the related analgesic circuit may serve as therapeutic targets for neuropathic pain. In contrast, MCC Cg1Glu have an opposite role in pain modulation and become hyperactive after nerve injury. The present study provides novel evidence for the concept that neuropathic pain is associated with the dysfunction of endogenous pain modulatory system and new perspective on the treatment of neuropathic pain.