Dorsal horn circuits for mechanical allodynia

疼痛仍然是一个主要的临床问题，因为它的发病率很高，而且缺乏适当的治疗。 选择。由于缺乏对神经的了解，更有效的治疗方法的确定受到阻碍。 构成疼痛的电路和机制。这项提案中概述的工作重点是描绘背部 用于机械性异位痛觉的喇叭回路，这是一种常见的情况，在这种情况下，触摸或运动在 受伤。背角是躯体感觉信息整合的主要部位。它也是受伤的地方- 回路的诱导性变化会引起机械性异位痛觉。在阐明背角的研究中 机械性痛觉异常回路，我们已经确定了背角兴奋性中间神经元的群体 调解这种形式的痛苦。此外，我们提出了支持神经回路的概念的证据 根据损伤的性质不同，在背角调节机械性异位痛觉的作用也不同。因此， 这个项目的主要目标是描绘机械性痛觉异常背后的背角回路。 损伤类型、炎症性和神经性的背景。在目标1)中，我们将确定 兴奋性中间神经元群体是机械性痛觉异常所必需的 炎症性和神经性疼痛。在目标2)中，我们将扩展我们对背角电路的理解 在幼稚的条件下通过识别神经元与这些兴奋性中间神经元群相关 与它们单调连接。这张更详细的基本背角电路图将有助于 旨在确定由不同类型的疼痛引起的机械性超敏的关键变化 受伤。在目标3)中，我们将使用机械性异位痛觉的体外模型来测试这些兴奋性的作用。 炎症性和神经病理性疼痛模型中的中间神经元数量。这将使我们能够评估 突触水平，这些神经元在损伤类型背景下在机械性痛觉异常中的作用。班级 I层投射神经元的传入和数量也将被评估。这些新颖的研究将提供 一个关键的解剖学框架，用来推进神经元和突触的分子和突触水平的研究 机械性痛觉异常的机制以及产生新的治疗策略。

Pain continues to be a major clinical problem due to its high prevalence and lack of adequate treatment options. The identification of more effective therapies is hampered by a lack of understanding of the neural circuits and mechanisms that underlie pain. Work outlined in this proposal is focused on delineating the dorsal horn circuits for mechanical allodynia, a common condition in which touch or movement become painful after injury. The dorsal horn is a major site for the integration of somatosensory information. It is also where injury- induced changes in the circuitry give rise to mechanical allodynia. In studies to elucidate the dorsal horn mechanical allodynia circuits, we have identified populations of dorsal horn excitatory interneurons that mediate this form of pain. Additionally, we present evidence supporting the concept that the neural circuitry that mediates mechanical allodynia in the dorsal horn differs depending on the nature of the injury. Thus, the overarching goal of this project is to delineate the dorsal horn circuits underlying mechanical allodynia in the context of the type of injury, inflammatory and neuropathic. In Aim 1) we will determine whether the populations of excitatory interneurons are required for mechanical allodynia produced by models of inflammatory and neuropathic pain. In Aim 2) we will expand our understanding of the dorsal horn circuitry related to these excitatory interneuron populations under naïve conditions by identifying the neurons monosynaptically connected to them. This more detailed picture of the basic dorsal horn circuitry will facilitate experiments aimed at identifying key changes that underlie mechanical allodynia caused by different types of injuries. In Aim 3) we will use an in vitro model of mechanical allodynia to test the role of these excitatory interneuron populations in inflammatory and neuropathic pain models. This will allow us to assess on a synaptic level the role of these neurons in mechanical allodynia in the context of injury-type. Classes of afferents and populations of lamina I projection neurons will also be assessed. These novel studies will provide a critical anatomical framework with which to advance molecular- and synaptic-level studies of the neurons and mechanisms that underlie mechanical allodynia as well as generate new therapeutic strategies.