Lipid signaling in supraspinal pain pathways

项目摘要 中央杏仁核（CeA）中的神经元有助于疼痛调制。然而，他们对感官的贡献- 慢性疼痛的辨别和/或情绪情感维度，也不是它们的神经化学调制， 明白我们使用切片记录和行为的初步数据为这个想法提供了一个令人信服的前提 靶向生物活性溶血磷脂受体的药物，鞘氨醇-1-磷酸（S1 P）作用于 CeA抑制炎性和神经性疼痛。这为我们的长期目标奠定了基础， 脂质信号如何控制急性和慢性疼痛的脊髓上控制。这项建议的目的是 确定多种疼痛模型中分子特异性CeA神经元的神经生理学变化（目的1）， 阐明S1 P信号对CeA特定亚群的内在和突触兴奋性的影响 神经元（目的2），并确定是否S1 PR激动CeA是镇痛的炎症模型， 神经性疼痛（目标3）。在目标1中，我们使用转基因小鼠品系、电生理学和光遗传学来测试 组织或神经损伤降低CeA神经元特定亚类兴奋性的假设， 他们的分子特征在目标2中，我们检验了S1 P信号的激活增加兴奋性的假设。 和突触连接的分子不同的CeA神经元的人口。在目标3中，我们使用颅内 药物输注和化学遗传学，以检验CeA中S1 P受体的激活减弱 炎性和神经性疼痛。这些概念的实验支持 将促进现有的（例如FDA批准的芬戈莫德）和新的S1 PR化合物的开发， 治疗慢性疼痛。

PROJECT SUMMARY Neurons in the central amygdala (CeA) contribute to pain modulation. However, their contribution to the sensory- discriminative and/or emotional-affective dimensions of chronic pain, nor their neurochemical modulation, are understood. Our preliminary data using slice recordings and behavior provide a compelling premise for the idea that drugs targeting the receptors for the bioactive lysophospholipid, sphingosine-1-phosphate (S1P) act within the CeA to inhibit inflammatory and neuropathic pain. This sets the stage for our long-term goal to understand how lipid signaling controls the supraspinal control of acute and chronic pain. The objectives of this proposal are to: determine neurophysiological changes to molecular specific CeA neurons in multiple models of pain (Aim 1), elucidate the effects of S1P signaling on the intrinsic and synaptic excitability of defined subpopulations of CeA neurons (Aim 2), and determine if S1PR agonism in the CeA is analgesic in models of inflammatory and neuropathic pain (Aim 3). In Aim 1, we use transgenic mouse lines, electrophysiology, and optogenetics to test the hypotheses that tissue or nerve injury reduces excitability of specific subclasses of CeA neurons based on their molecular profile. In Aim 2, we test the hypotheses that activation of S1P signaling increases the excitability and synaptic connectivity within a population of molecularly distinct CeA neurons. In Aim 3, we use intracranial drug infusions and chemogenetics to test the hypothesis that activation of S1P receptors in the CeA attenuates inflammatory and neuropathic pain via a specific subtype of CeA neuron. Experimental support of these concepts will facilitate the development of existing (e.g. FDA-approved fingolimod) and novel S1PR compounds for the treatment of chronic pain.