Cellular and molecular mechanisms undelying amygdala-dependent pain modulation

描述(由申请人提供)：慢性疼痛是人类患者的一个严重负担，困扰着超过30%的人口。虽然许多研究都集中在外周和脊髓对疼痛的控制上，但我对评估大脑局部的疼痛调制很感兴趣。杏仁核是焦虑、恐惧和学习行为情绪处理的重要部位，也是控制疼痛的高级部位。杏仁中央核(CEA)通过脊髓-桥脑-杏仁体痛觉通路接受伤害性信息输入，通过杏仁其他核团接受多模式感觉信息。最近，我们的团队已经确定了细胞外信号调节激酶(ERK)信号在小鼠CEA中的关键作用。CEA中ERK的激活既是炎性疼痛模型行为敏化所必需的，又足以在没有外周炎症的情况下产生对机械刺激的超敏反应。然而，CEA中ERK的上游激活物和下游效应物仍不清楚。有趣的是，通过CEA中的I组代谢性谷氨酸受体(MGluRs)发出的信号是关节炎疼痛的行为和细胞反应中的重要组成部分。在脊髓，I组mGluRs与ERK偶联，影响行为敏化和神经元兴奋性。因此，我们假设CEA I组mGluRs介导ERK信号的增加，以改变炎症过程中的行为敏感化，并调节杏仁核中神经元的兴奋性。在我们的第一个具体目标中，我们将使用药理学技术来评估I组mGluR信号在调节ERK激活和行为敏化中的作用。在第二个目标中，我们将使用电生理技术来评估mGluR和ERK对神经元兴奋性的影响。 公共卫生相关性：我们对大脑中疼痛调制的了解不足是慢性疼痛治疗效果相对较差的部分原因。这项研究计划旨在通过重点研究杏仁核中调节疼痛的信号机制，来研究杏仁核在慢性疼痛中的作用。杏仁核是大脑中参与疼痛情绪反应的区域。确定这一区域的疼痛调节机制将有助于确定新治疗开发的治疗靶点。

DESCRIPTION (provided by applicant): Chronic pain presents a serious burden to human patients afflicting over 30% of the population. Although much research has focused on the peripheral and spinal cord control of pain, I am Interested In evaluating brain-localized pain modulation. The amygdala, an important site for emotional processing of anxiety, fear and learning behaviors, is well situated to be a higher order locus for the control of pain. The central nucleus of the amygdala (CeA) receives nociceptive Inputs via the spino-ponto- amygdaloid pain pathway and polymodal sensory Information via other amygdalar nuclei. Recently, our group has identified a critical role for extracellular-signal regulated kinase (ERK) signaling in the CeA of mice. ERK activation in the CeA is both necessary for behavioral sensitization in a model of inflammatory pain and sufficient to produce hypersensitivity to mechanical stimuli in the absence of peripheral inflammation. However, the upstream activators and downstream effectors of ERK in the CeA remain unknown. Interestingly, signaling through group I metabotropic glutamate receptors (mGluRs) in the CeA serves as an important component in the behavioral and cellular response to arthritic pain. In the spinal cord, group I mGluRs couple to ERK to affect behavioral sensitization and neuronal excitability. Therefore, we hypothesize that CeA group I mGluRs mediate increases In ERK signaling to alter behavioral sensitization during inflammation and to modulate neuronal excitability in the amygdala. In our first specific aim, we will use pharmacological techniques to evaluate the role of group I mGluR signaling in modulating ERK activation and behavioral sensitization. In aim two, we will use electrophysiological techniques to evaluate the effect of mGluR and ERK on neuronal excitability. PUBLIC HEALTH RELEVANCE: Our poor understanding of pain modulation In the brain is partially responsible for the relatively poor efficacy of treatments for chronic pain. This research plan Is designed to study the role of the amygdala, a brain region Involved In emotional responses to pain, in chronic pain by focusing on the signaling mechanisms in the amygdala that regulate pain. Identification of the mechanisms of pain modulation in this area will aid in the identification of therapeutic targets for novel treatment development.