Cortico-striatal plasticity in the transition to chronic pain

描述(申请人提供)：在本申请中，我们认为从急性疼痛过渡到慢性疼痛的机制关键取决于大脑的情绪和动机学习和记忆回路，即皮质纹状体系统的特性。这是一个激进的 背离经典的疼痛研究传统，强调伤害性感受的编码和表征机制。我们提供与这一想法一致的人类和动物模型数据，并建议通过测试防止过渡到慢性疼痛的药物治疗策略来解开潜在机制并将这些信息转化为临床应用。我们招募了Surmeier博士(世界著名的纹状体生理学和重组专家)和Martina博士(具有大脑分子和电生理学研究专长的年轻科学家)与阿普卡里安合作开展这一项目，菲尔兹博士和祖比埃塔博士担任该项目的顾问。在目标1中，我们结合了三个合作实验室(Apkarian，Martina，Surmeier)的专业知识，将大规模脑成像结果与细胞、分子和电生理变化联系起来，我们预测在啮齿动物从周围神经损伤到神经病理性疼痛样行为的转变过程中，皮质纹状体经历了这些变化。在目标2中，我们比较了几种潜在的药物，以防止在大鼠模型中过渡到慢性疼痛样行为。在目标3中，我们使用人类早期临床试验中的最佳候选药物，结合脑成像，预防过渡到慢性疼痛。这项研究的成功完成将极大地改变目前关于疼痛慢性化的脑机制的概念，并为预防向慢性疼痛的过渡提供新的治疗策略概念。

DESCRIPTION (provided by applicant): In this application we argue that mechanisms of transition from acute to chronic pain critically depend on brain emotional and motivational learning and memory circuit, namely the properties of the corticostriatal system. This is a radical departure from the classic pain research tradition, which emphasizes mechanisms of nociceptive encoding and representation. We provide human and animal model data consistent with the idea, and propose unraveling underlying mechanisms and translating this information to clinical application by testing a drug treatment strategy for preventing transition to chronic pain We recruit Dr. Surmeier (a world renowned expert on the physiology and reorganization of the striatum) and Dr. Martina (a young scientist with expertise in molecular and electrophysiological studies of the brain), to collaborate with Apkarian on this project, and Drs. Fields and Zubieta act as consultants for the project. In Aim 1 we combine the expertise of the three collaborating labs (Apkarian, Martina, Surmeier) to link large-scale brain imaging outcomes to cellular, molecular, and electrophysiological changes that we predict the corticostriatal undergoes in the transition from peripheral nerve injury to neuropathic pain-like behavior in rodents. In Aim 2 we compare among potential drugs for preventing transition to chronic pain-like behavior in a rat model. In Aim 3 we use the best candidate drug in a human early phase clinical trial, combined with brain imaging, for prevention of transition to chronic pain. The successful completion of the study should dramatically change current notions regarding brain mechanisms of pain chronification, and provide a new concept of treatment strategy for preventing the transition to chronic pain.