Spinal Nmur2-positive Neurons Play a Crucial Role in Mechanical Itch

IF 4 2区 医学 Q1 CLINICAL NEUROLOGY
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Abstract

The dorsal spinal cord is crucial for the transmission and modulation of multiple somatosensory modalities, such as itch, pain, and touch. Despite being essential for the well-being and survival of an individual, itch and pain, in their chronic forms, have increasingly been recognized as clinical problems. Although considerable progress has been made in our understanding of the neurochemical processing of nociceptive and chemical itch sensations, the neural substrate that is crucial for mechanical itch processing is still unclear. Here, using genetic and functional manipulation, we identified a population of spinal neurons expressing neuromedin U receptor 2 (Nmur2+) as critical elements for mechanical itch. We found that spinal Nmur2+ neurons are predominantly excitatory neurons, and are enriched in the superficial laminae of the dorsal horn. Pharmacogenetic activation of cervical spinal Nmur2+ neurons evoked scratching behavior. Conversely, the ablation of these neurons using a caspase-3-based method decreased von Frey filament-induced scratching behavior without affecting responses to other somatosensory modalities. Similarly, suppressing the excitability of cervical spinal Nmur2+ neurons via the overexpression of functional Kir2.1 potassium channels reduced scratching in response to innocuous mechanical stimuli, but not to pruritogen application. At the lumbar level, pharmacogenetic activation of these neurons evoked licking and lifting behaviors. However, ablating these neurons did not affect the behavior associated with acute pain. Thus, these results revealed the crucial role of spinal Nmur2+ neurons in mechanical itch. Our study provides important insights into the neural basis of mechanical itch, paving the way for developing novel therapies for chronic itch.

Perspective

Excitatory Nmur2+ neurons in the superficial dorsal spinal cord are essential for mechanical but not chemical itch information processing. These spinal Nmur2+ neurons represent a potential cellular target for future therapeutic interventions against chronic itch. Spinal and supraspinal Nmur2+ neurons may play different roles in pain signal processing.

脊髓 Nmur2 阳性神经元在机械瘙痒中发挥着关键作用。
背侧脊髓对痒、痛和触觉等多种躯体感觉模式的传递和调节至关重要。尽管痒和痛对个体的福祉和生存至关重要,但它们的慢性形式已被越来越多的人视为临床问题。尽管我们对痛觉和化学痒觉的神经化学处理的理解已经取得了相当大的进展,但对机械痒处理至关重要的神经基质仍然不清楚。在这里,我们利用遗传和功能操作,确定了表达神经生长因子 U 受体 2(Nmur2+)的脊髓神经元群是机械痒的关键因素。我们发现,脊髓 Nmur2+ 神经元主要是兴奋性神经元,富集在背角浅层。药物激活颈椎Nmur2+神经元可诱发搔抓行为。相反,使用基于caspase-3的方法消融这些神经元会减少von Frey丝诱发的搔抓行为,但不会影响对其他躯体感觉模式的反应。同样,通过过表达功能性Kir2.1钾通道抑制颈椎Nmur2+神经元的兴奋性,可减少对无害机械刺激的搔抓行为,但不影响对瘙痒原的应用。在腰椎水平,这些神经元的药物基因激活会诱发舔和抬举行为。然而,消融这些神经元并不会影响与急性疼痛相关的行为。因此,这些结果揭示了脊髓 Nmur2+ 神经元在机械痒中的关键作用。我们的研究为了解机械性痒的神经基础提供了重要见解,为开发治疗慢性痒的新型疗法铺平了道路。观点:浅表背侧脊髓中的兴奋性Nmur2+神经元是机械痒信息处理的关键,但不是化学痒信息处理的关键。这些脊髓 Nmur2+ 神经元是未来治疗慢性瘙痒的潜在细胞靶点。脊髓和脊髓上Nmur2+神经元在疼痛信号处理中可能扮演着不同的角色。
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来源期刊
Journal of Pain
Journal of Pain 医学-临床神经学
CiteScore
6.30
自引率
7.50%
发文量
441
审稿时长
42 days
期刊介绍: The Journal of Pain publishes original articles related to all aspects of pain, including clinical and basic research, patient care, education, and health policy. Articles selected for publication in the Journal are most commonly reports of original clinical research or reports of original basic research. In addition, invited critical reviews, including meta analyses of drugs for pain management, invited commentaries on reviews, and exceptional case studies are published in the Journal. The mission of the Journal is to improve the care of patients in pain by providing a forum for clinical researchers, basic scientists, clinicians, and other health professionals to publish original research.
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