The neuroaxis of pain: Peripheral transduction to central integration

急性疼痛是一种不愉快但重要的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，这导致人与人之间的高度差异。在生物学上，疼痛严重依赖于解剖学基质和生理过程，其：i）将有害刺激转化为外周中的神经信号，ii）在薄髓鞘和无髓鞘传入中传导神经冲动，以及iii）在沿着神经轴的各个点整合信号（即，脊髓到大脑）。这些统称为“伤害感受”。伤害感受的一个标志是在没有增加伤害性刺激强度的情况下放大疼痛的能力。通过敏化过程，疼痛放大的过程发生在外周和中枢，在伤害感受器水平和脊髓背角。迄今为止，关于疼痛致敏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。我的研究的首要长期目标是揭示伤害感受中涉及的离散神经解剖学基底和神经生理学过程。这将通过探索伤害性刺激如何在外周转导，在外周传入进行，整合在脊髓中，并在健康参与者的大脑中处理来实现。在接下来的5年里，我提出的NSERC发现平台将主要关注疼痛放大的主题。短期目标为：1。描述外周感受器在痛觉致敏中的功能作用。了解痛觉敏感化与突触外谷氨酸受体的关系。检查疼痛对大脑中静息谷氨酸动力学的影响我的NSERC发现补助金提案整合了各种定量方法来评估疼痛，再加上药理学方法来操纵敏化过程。主要合作包括UBC的其他NSERC资助的研究人员，包括Blouin博士和Laule博士，以及苏黎世大学的同事（例如，Schweinhardt和胡布利博士）。HQP从本科生到博士后研究员将在研究密集型环境中进行培训，由3个优先UBC研究中心（即，ICORD，DMCBH和UBC MRI研究中心），在一个配备齐全的实验室进行拟议的实验。此外，他们将发展疼痛，磁共振光谱，脑电图和定量感觉测试的实验模型的技能，并定位于在学术和工业上取得成功。

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.