A subset of spinal dorsal horn interneurons crucial for gating touch-evoked pain-like behavior
A subset of spinal dorsal horn interneurons crucial for gating touch-evoked pain-like behavior
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DOI：
10.1073/pnas.2021220118
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发表时间：
2021-01-19
影响因子：
11.1
通讯作者：
Tsuda, Makoto
中科院分区：
文献类型：
--
作者：
Tashima, Ryoichi;Koga, Keisuke;Tsuda, Makoto
神经性疼痛的主要难治性症状是机械性异常性疼痛，即通过低阈值机械感受器如A β纤维由无害刺激引起的疼痛。然而，A β纤维衍生的信号转化为疼痛的机制仍然不完全清楚。在这里，我们确定了脊髓背角（SDH）中的抑制性中间神经元的一个子集，该子集由包含神经肽Y启动子（AAV-NpyP（+））的腺相关病毒载体操作，并表明AAV-NpyP（+）SDH中间神经元的特异性消融或沉默将触觉感知A β纤维衍生的信号转化为抗吗啡疼痛样行为反应。AAV-NpyP（+）神经元接受来自A β纤维的兴奋性输入，并将抑制性GABA信号传递到投射到脑的I层神经元。在由周围神经损伤引起的神经病理性疼痛模型中，AAV-NpyP（+）神经元表现出更深的静息膜电位，并且它们被A β纤维的兴奋受损。相反，在神经损伤大鼠中AAV-NpyP（+）神经元的化学发生激活逆转了A β纤维衍生的神经性疼痛样行为，其显示出吗啡抗性，并减少了包括板层I的浅表SDH的病理性神经元激活。这些发现表明，识别出的抑制性SDH中间神经元在将触摸传感A β纤维信号转换为疼痛样行为反应时起关键制动作用。因此，增强这些神经元的活性可能为治疗神经性异常性疼痛提供新的策略。
A cardinal, intractable symptom of neuropathic pain is mechanical allodynia, pain caused by innocuous stimuli via low-threshold mechanoreceptors such as A beta fibers. However, the mechanism by which A beta fiber-derived signals are converted to pain remains incompletely understood. Here we identify a subset of inhibitory interneurons in the spinal dorsal horn (SDH) operated by adeno-associated viral vectors incorporating a neuropeptide Y promoter (AAV-NpyP(+)) and show that specific ablation or silencing of AAV-NpyP(+) SDH interneurons converted touch-sensing A beta fiber-derived signals to morphine-resistant pain-like behavioral responses. AAV-NpyP(+) neurons received excitatory inputs from A beta fibers and transmitted inhibitory GABA signals to lamina I neurons projecting to the brain. In a model of neuropathic pain developed by peripheral nerve injury, AAV-NpyP(+) neurons exhibited deeper resting membrane potentials, and their excitation by A beta fibers was impaired. Conversely, chemogenetic activation of AAV-NpyP(+) neurons in nerve-injured rats reversed A beta fiber-derived neuropathic pain-like behavior that was shown to be morphine-resistant and reduced pathological neuronal activation of superficial SDH including lamina I. These findings suggest that identified inhibitory SDH interneurons that act as a critical brake on conversion of touch-sensing A beta fiber signals into pain-like behavioral responses. Thus, enhancing activity of these neurons may offer a novel strategy for treating neuropathic allodynia.