Optogenetic Activation of Non-Nociceptive Aβ Fibers Induces Neuropathic Pain-Like Sensory and Emotional Behaviors after Nerve Injury in Rats.
Optogenetic Activation of Non-Nociceptive Aβ Fibers Induces Neuropathic Pain-Like Sensory and Emotional Behaviors after Nerve Injury in Rats.
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DOI：
10.1523/eneuro.0450-17.2018
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发表时间：
2018-01
期刊：
影响因子：
3.4
通讯作者：
Tsuda M
中科院分区：
文献类型：
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作者：
Tashima R;Koga K;Sekine M;Kanehisa K;Kohro Y;Tominaga K;Matsushita K;Tozaki-Saitoh H;Fukazawa Y;Inoue K;Yawo H;Furue H;Tsuda M
神经性疼痛是由周围神经损伤（PNI）引起的。一个标志性症状是异常性疼痛（由正常无害的刺激引起的疼痛），但其机制基础仍然难以捉摸。值得注意的是，选择性刺激非伤害性初级传入Aβ纤维是否确实引起PNI后的神经性疼痛样感觉和情绪行为尚不清楚，因为缺乏工具来操纵清醒、自由活动的动物中的Aβ纤维功能。在这项研究中，我们使用了一种转基因大鼠品系，该品系能够通过光激活通道（channelrhodopsin-2; ChR 2）刺激非伤害性Aβ纤维。我们发现，光照到这些PNI大鼠的足底皮肤会引起疼痛样的戒断行为，这种行为对吗啡有抵抗力。光照PNI大鼠皮肤增加脊髓背角（SDH）板层I神经元的数量阳性的活动标志物（c-Fos和磷酸化细胞外信号调节蛋白激酶; pERK）。全细胞记录显示，PNI后光遗传学Aβ纤维刺激引起板层I神经元的兴奋，而板层I神经元通常被这种刺激沉默。此外，照亮PNI大鼠的后爪导致中央杏仁核神经元的激活，并产生对照明的厌恶。因此，这些发现提供了第一个证据，即PNI大鼠中初级传入Aβ纤维的光遗传学激活产生对吗啡治疗有抗性的板层I神经元和神经性疼痛样行为的兴奋。这一方法可能为研究PNI后Aβ纤维介导的神经性异常性疼痛的感觉和情绪方面的回路和行为以及发现治疗神经性疼痛的新药物提供新的途径。
Neuropathic pain is caused by peripheral nerve injury (PNI). One hallmark symptom is allodynia (pain caused by normally innocuous stimuli), but its mechanistic underpinning remains elusive. Notably, whether selective stimulation of non-nociceptive primary afferent Aβ fibers indeed evokes neuropathic pain-like sensory and emotional behaviors after PNI is unknown, because of the lack of tools to manipulate Aβ fiber function in awake, freely moving animals. In this study, we used a transgenic rat line that enables stimulation of non-nociceptive Aβ fibers by a light-activated channel (channelrhodopsin-2; ChR2). We found that illuminating light to the plantar skin of these rats with PNI elicited pain-like withdrawal behaviors that were resistant to morphine. Light illumination to the skin of PNI rats increased the number of spinal dorsal horn (SDH) Lamina I neurons positive to activity markers (c-Fos and phosphorylated extracellular signal-regulated protein kinase; pERK). Whole-cell recording revealed that optogenetic Aβ fiber stimulation after PNI caused excitation of Lamina I neurons, which were normally silent by this stimulation. Moreover, illuminating the hindpaw of PNI rats resulted in activation of central amygdaloid neurons and produced an aversion to illumination. Thus, these findings provide the first evidence that optogenetic activation of primary afferent Aβ fibers in PNI rats produces excitation of Lamina I neurons and neuropathic pain-like behaviors that were resistant to morphine treatment. This approach may provide a new path for investigating circuits and behaviors of Aβ fiber-mediated neuropathic allodynia with sensory and emotional aspects after PNI and for discovering novel drugs to treat neuropathic pain.