Université Clermont Auvergne, Inserm, Neuro-Dol, F-63000 Clermont-Ferrand, France, and
Université Clermont Auvergne, Inserm, Neuro-Dol, F-63000 Clermont-Ferrand, France, and.
J Neurosci. 2018 Dec 5;38(49):10489-10504. doi: 10.1523/JNEUROSCI.1294-18.2018. Epub 2018 Oct 24.
Mechanical allodynia, a widespread pain symptom that still lacks effective therapy, is associated with the activation of a dorsally directed polysynaptic circuit within the spinal dorsal horn (SDH) or medullary dorsal horn (MDH), whereby tactile inputs into deep SDH/MDH can gain access to superficial SDH/MDH, eliciting pain. Inner lamina II (II) interneurons expressing the γ isoform of protein kinase C (PKCγ) are key elements for allodynia circuits, but how they operate is still unclear. Combining behavioral, electrophysiological, and morphological approaches in an adult rat model of facial inflammatory pain (complete Freund's adjuvant, CFA), we show that the mechanical allodynia observed 1 h after CFA injection is associated with the following (1) sensitization (using ERK1/2 phosphorylation as a marker) and (2) reduced dendritic arborizations and enhanced spine density in exclusively PKCγ interneurons, but (3) depolarized resting membrane potential (RMP) in all lamina II PKCγ/PKCγ interneurons. Blocking MDH 5HT receptors (5-HTR) prevents facial mechanical allodynia and associated changes in the morphology of PKCγ interneurons, but not depolarized RMP in lamina II interneurons. Finally, activation of MDH 5-HTR in naive animals is enough to reproduce the behavioral allodynia and morphological changes in PKCγ interneurons, but not the electrophysiological changes in lamina II interneurons, induced by facial inflammation. This suggests that inflammation-induced mechanical allodynia involves strong morphological reorganization of PKCγ interneurons via 5-HTR activation that contributes to open the gate for transmission of innocuous mechanical inputs to superficial SDH/MDH pain circuitry. Preventing 5-HTR-induced structural plasticity in PKCγ interneurons might represent new avenues for the specific treatment of inflammation-induced mechanical hypersensitivity. Inflammatory or neuropathic pain syndromes are characterized by pain hypersensitivity such as mechanical allodynia (pain induced by innocuous mechanical stimuli). It is generally assumed that mechanisms underlying mechanical allodynia, because they are rapid, must operate at only the level of functional reorganization of spinal or medullary dorsal horn (MDH) circuits. We discovered that facial inflammation-induced mechanical allodynia is associated with rapid and strong structural remodeling of specifically interneurons expressing the γ isoform of protein kinase C (PKCγ) within MDH inner lamina II. Moreover, we elucidated a 5-HT receptor to PKCγ/ERK1/2 pathway leading to the behavioral allodynia and correlated morphological changes in PKCγ interneurons. Therefore, descending 5-HT sensitize PKCγ interneurons, a putative "gate" in allodynia circuits, via 5-HT receptor-induced structural reorganization.
机械性痛觉过敏是一种广泛存在的疼痛症状，目前仍缺乏有效的治疗方法，其与脊髓背角（SDH）或延髓背角（MDH）中背向多突触回路的激活有关，在此过程中，深部 SDH/MDH 的触觉输入可以进入浅部 SDH/MDH，引发疼痛。表达蛋白激酶 C（PKC）γ同工型的内板 II（II）中间神经元是痛觉过敏回路的关键组成部分，但它们的作用机制尚不清楚。我们在成年大鼠面部炎症性疼痛模型（完全弗氏佐剂，CFA）中结合行为学、电生理学和形态学方法，发现 CFA 注射后 1 小时观察到的机械性痛觉过敏与以下情况有关：（1）敏化（以 ERK1/2 磷酸化作为标记）和（2）仅 PKCγ 中间神经元的树突分支减少和棘突密度增加，但（3）所有 II 板 PKCγ/PKCγ 中间神经元的静息膜电位（RMP）去极化。阻断 MDH 5-羟色胺受体（5-HTR）可预防面部机械性痛觉过敏和 PKCγ 中间神经元形态的改变，但不能预防 II 板中间神经元的 RMP 去极化。最后，在正常动物中激活 MDH 5-HTR 足以重现行为性痛觉过敏和 PKCγ 中间神经元的形态改变，但不能重现面部炎症引起的 II 板中间神经元的电生理学改变。这表明，炎症诱导的机械性痛觉过敏涉及通过 5-HTR 激活对 PKCγ 中间神经元进行强烈的形态重建，这有助于打开无害机械输入到浅部 SDH/MDH 疼痛回路的通路。防止 PKCγ 中间神经元中 5-HTR 诱导的结构可塑性可能为炎症诱导的机械性敏感性的特异性治疗提供新途径。炎症或神经病理性疼痛综合征的特征是疼痛敏感性增加，如机械性痛觉过敏（无害机械刺激引起的疼痛）。一般认为，机械性痛觉过敏的机制，因为它们是快速的，必须仅在脊髓或延髓背角（MDH）电路的功能重组水平上起作用。我们发现，面部炎症诱导的机械性痛觉过敏与 MDH 内板 II 内特异性表达蛋白激酶 C（PKC）γ同工型的中间神经元的快速和强烈的结构重塑有关。此外，我们阐明了一条 5-HT 受体到 PKCγ/ERK1/2 途径，该途径导致行为性痛觉过敏和相关的 PKCγ 中间神经元形态变化。因此，下行 5-HT 通过 5-HT 受体诱导的结构重排使 PKCγ 中间神经元敏化，成为痛觉过敏回路中的一个“门”。
