The neuroaxis of pain: Peripheral transduction to central integration

急性疼痛是一种令人不快但具有生命力和保护性的躯体感觉体验，在日常生活中很常见。已知有许多因素会影响疼痛体验，这导致了人与人之间高度的可变性。从生物学上讲，疼痛主要依赖于以下解剖基础和生理过程：i)将伤害性刺激转化为外周的神经信号，ii)在稀有髓鞘和无髓鞘传入中传导神经冲动，iii)整合神经轴上不同点的信号(即脊髓到脑)。这些统称为“伤害性感受”。伤害性感觉的一个特点是在不增加伤害性刺激强度的情况下放大疼痛的能力。放大疼痛的过程发生在外周和中枢，在伤害性感受器水平和脊髓背角，通过敏化过程。到目前为止，关于疼痛敏感化的知识主要是在动物模型中产生的。将这些研究转移到人类身上涉及详细的神经生理学和解剖学研究，这需要专门的培训、设备和技能。我研究的主要长期目标是揭示涉及伤害性感受的离散神经解剖学基础和神经生理学过程。这将通过探索有害刺激是如何在外周传递、在外周传入、整合到脊髓和在健康参与者的大脑中进行处理的方式来实现的。在接下来的5年里，我提出的NSERC发现平台将主要专注于疼痛放大的主题。短期目标将：1.表征外周受体在疼痛敏化中的功能作用2.了解疼痛敏化和突触外谷氨酸受体之间的关系3.检查疼痛对大脑中静息谷氨酸动态的影响我的NSERC发现拨款提案整合了各种量化方法来评估疼痛，并结合药理学方法来操纵敏化所涉及的过程。主要合作伙伴包括UBC由NSERC资助的其他研究人员，包括Blouin博士和Laule博士，以及苏黎世大学的同事(例如Schweinhardt博士和Hubli博士)。从本科生到博士后研究员的HQP将在研究密集的环境中进行培训，由3个优先的UBC研究中心(即ICORD、DMCBH和UBC MRI研究中心)支持，在一个完全具备进行拟议实验的设备的实验室中进行培训。此外，他们还将发展疼痛实验模型、磁共振波谱、脑电和定量感觉测试方面的技能，并为在学术和行业中取得成功做好准备。

Acute pain is an unpleasant but vital and protective somatosensory experience, common to everyday life. A number of factors are known to influence the experience of pain, which contributes to a high degree of person-to-person variability. Biologically, pain critically depends on anatomical substrates and physiological processes that: i) transduce a noxious stimulus into neural signals in the periphery, ii) conduct neural impulses in thinly myelinated and unmyelinated afferents, and iii) integrate signals at various points along the neuroaxis (i.e., spinal cord to brain). Collectively, these are termed "nociception". A hallmark of nociception is a capacity to amplify pain in the absence of increasing noxious stimulation intensity. The process of amplifying pain occurs peripherally and centrally, at the level of the nociceptors and in the dorsal horn of the spinal cord, through processes of sensitization. To date, knowledge regarding the sensitization of pain have been primary generated in animal models. Moving these investigations into humans involves detailed neurophysiological and anatomical studies, which require specialized training, equipment, and skills. The overarching, long-term objective of my research is to reveal discrete neuroanatomical substrates and neurophysiological processes involved in nociception. This will be achieved by way of exploring how noxious stimuli are transduced in the periphery, conducted in peripheral afferents, integrated in the spinal cord, and processed in the brain of healthy participants. In the next 5 years, my proposed NSERC Discovery platform will primarily focus on the theme of pain amplification. Short-term objectives will: 1.Characterize the functional role of peripheral receptors in the sensitization of pain 2. Understand the relationship between sensitization of pain and extrasynaptic glutamate receptors 3. Examine the effect of pain on resting glutamate dynamics in the brain My NSERC Discovery Grant proposal integrates a variety of quantitative methods to assess pain, coupled with pharmacological approaches to manipulate processes involved in sensitization. Key collaborations include other NSERC funded researchers at UBC, including Drs. Blouin and Laule, as well as colleagues at the University of Zurich (e.g., Drs. Schweinhardt and Hubli). HQP from undergraduates to Postdoctoral Fellows will train in a research intensive environment, supported by 3 priority UBC research centres (i.e., ICORD, DMCBH, and the UBC MRI Research Centre), in a lab that is fully equipped to conduct the proposed experiments. Furthermore, they will develop skills in experimental models of pain, magnetic resonance spectroscopy, electroencephalography, and quantitative sensory testing, and be positioned to succeed in academics and industry.