Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, Oregon 97239-3098
J Neurosci. 2022 Mar 9;42(10):1958-1973. doi: 10.1523/JNEUROSCI.1860-21.2021. Epub 2022 Jan 19.
The superficial dorsal horn (SDH) of the spinal cord represents the first site of integration between innocuous and noxious somatosensory stimuli. According to gate control theory, diverse populations of excitatory and inhibitory interneurons within the SDH are activated by distinct sensory afferents, and their interplay determines the net nociceptive output projecting to higher pain centers. Although specific SDH cell types are ill defined, numerous classifications schemes find that excitatory and inhibitory neurons fundamentally differ in their morphology, electrophysiology, neuropeptides, and pain-associated plasticity; yet little is known about how these neurons respond over a range of natural innocuous and noxious stimuli. To address this question, we applied an imaging approach in male mice where the genetically encoded calcium indicator GCaMP6s was expressed either in vGluT2-positive excitatory or vIAAT-positive inhibitory neurons. We found that inhibitory neurons were markedly more sensitive to innocuous touch than excitatory neurons but still responded dynamically over a wide range of noxious mechanical stimuli. Inhibitory neurons were also less sensitive to thermal stimuli than their excitatory counterparts. In a capsaicin model of acute pain sensitization, the responses of excitatory neurons were significantly potentiated to innocuous and noxious mechanical stimuli, whereas inhibitory neural responses were only depressed to noxious stimuli. These findings show that excitatory and inhibitory SDH neurons diverge considerably in their somatosensory responses and plasticity, as postulated by gate control theory. Gate control theory posits that opposing spinal excitatory and inhibitory neurons, differently tuned across somatosensory modalities, determine the net nociceptive output to higher pain centers. Little is known about how natural stimuli activate these two neural populations. This study applied an calcium imaging approach to genetically target these neurons and contrast their responses over a range of innocuous and noxious mechanical and thermal stimuli. Compared with excitatory neurons, we found that inhibitory neurons are more sensitive to innocuous touch and far less sensitive to thermal stimuli. An acute model of pain also revealed that these subtypes undergo divergent mechanosensory plasticity. Our data provide important and novel insights for gate-control inspired models of pain processing.
脊髓的浅层背角（SDH）代表无害和有害躯体感觉刺激整合的第一部位。根据门控理论，SDH 内不同的兴奋性和抑制性中间神经元群体被不同的感觉传入激活，它们的相互作用决定了投射到更高疼痛中心的净伤害性输出。尽管特定的 SDH 细胞类型尚未明确界定，但许多分类方案发现，兴奋性和抑制性神经元在形态、电生理学、神经肽和与疼痛相关的可塑性方面存在根本差异；然而，对于这些神经元在一系列自然无害和有害刺激下的反应知之甚少。为了解决这个问题，我们在雄性小鼠中应用了一种成像方法，其中遗传编码钙指示剂 GCaMP6s 表达在 vGluT2 阳性兴奋性神经元或 vIAAT 阳性抑制性神经元中。我们发现，抑制性神经元对无害触摸的敏感性明显高于兴奋性神经元，但对广泛的有害机械刺激仍能动态反应。抑制性神经元对热刺激的敏感性也低于其兴奋性对应物。在辣椒素诱导的急性痛觉敏化模型中，兴奋性神经元对无害和有害机械刺激的反应显著增强，而抑制性神经元的反应仅对有害刺激受到抑制。这些发现表明，兴奋性和抑制性 SDH 神经元在躯体感觉反应和可塑性方面存在很大差异，这与门控理论假设一致。门控理论假设，不同感觉模态下不同调谐的脊髓兴奋性和抑制性神经元决定了投射到更高疼痛中心的净伤害性输出。关于自然刺激如何激活这两种神经元群体知之甚少。本研究应用钙成像方法对这些神经元进行基因靶向，并对比它们对一系列无害和有害机械和热刺激的反应。与兴奋性神经元相比，我们发现抑制性神经元对无害触摸更敏感，对热刺激的敏感性要低得多。急性疼痛模型也揭示了这两种亚型经历了不同的机械感觉可塑性。我们的数据为基于门控理论的疼痛处理模型提供了重要的新见解。
