Functional and anatomical analyses of active spinal circuits in a mouse model of chronic pain.
Functional and anatomical analyses of active spinal circuits in a mouse model of chronic pain.
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DOI：
10.1097/j.pain.0000000000003068
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发表时间：
2023-10
期刊：
影响因子：
7.4
通讯作者：
Katarzyna M Targowska-Duda;Darian Peters;Jason L. Marcus;Gilles Zribi;L. Toll;Akihiko Ozawa
中科院分区：
文献类型：
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作者：
Katarzyna M Targowska-Duda;Darian Peters;Jason L. Marcus;Gilles Zribi;L. Toll;Akihiko Ozawa
摘要经过几十年的努力，阐明疼痛的机制，包括药理学、神经解剖学和生理学的研究，已经为伤害性信息如何从外周传递到大脑和接收伤害性信号的位置提供了深刻的见解。然而，关于在不同的神经环境中，哪些特定的刺激依赖激活的神经元有区别地唤起同源疼痛行为，我们知之甚少。在这里，我们使用Fos2A-iCreer(TRAP2)小鼠，阐明了由疼痛刺激激活的脊髓神经元的数量，以确定慢性疼痛依赖激活的神经元亚群。我们发现，与假手术组相比，脊神经结扎组小鼠脊髓中有大量神经元被正常的非痛性刺激所激活。热痛觉过敏可见I、II外层神经元激活。在机械痛觉超敏和热痛觉过敏条件下，II板层内侧均有大量神经元被激活，而机械痛觉超敏往往是唯一激活II板层内背部神经元的刺激。使用脊髓细胞标记物的神经解剖学分析发现，机械性痛觉过敏和热痛觉过敏都招募了大量的脊髓抑制神经元。有趣的是，表达钙维A、钙结合蛋白和小白蛋白的脊髓神经元在不同的疼痛方式下被不同的激活(即机械性超感痛觉和热痛觉过敏)。对这些激活神经元的化学生成抑制显着且特别地降低了对与最初给予动物的刺激方式相关的疼痛刺激的反应。这些发现支持这样的观点，即潜在的伤害性信息传递的脊髓神经元集合经历了动态变化，以调节选择性疼痛反应。
ABSTRACT Decades of efforts in elucidating pain mechanisms, including pharmacological, neuroanatomical, and physiological studies have provided insights into how nociceptive information transmits from the periphery to the brain and the locations receiving nociceptive signals. However, little is known about which specific stimulus-dependent activated neurons, amongst heterogeneous neural environments, discriminatively evoke the cognate pain behavior. We here shed light on the population of neurons in the spinal cord activated by a painful stimulus to identify chronic pain-dependent activated neuronal subsets using Fos2A-iCreER (TRAP2) mice. We have found a large number of neurons activated by a normally nonpainful stimulus in the spinal cord of spinal nerve-ligated mice, compared with sham. Neuronal activation was observed in laminae I and II outer under heat hyperalgesia. A large number of neurons in laminae II inner were activated in both mechanical allodynia and heat hyperalgesia conditions, while mechanical allodynia tends to be the only stimulus that activates cells at lamina II inner dorsal region. Neuroanatomical analyses using spinal cell markers identified a large number of spinal inhibitory neurons that are recruited by both mechanical allodynia and heat hyperalgesia. Of interest, spinal neurons expressing calretinin, calbindin, and parvalbumin were activated differently with distinct pain modalities (ie, mechanical allodynia vs heat hyperalgesia). Chemogenetic inhibition of those activated neurons significantly and specifically reduced the response to the pain stimulus associated with the stimulus modality originally given to the animals. These findings support the idea that spinal neuronal ensembles underlying nociceptive transmission undergo dynamic changes to regulate selective pain responses.