Cellular Mechanisms of the Interaction Between Pain and Opioid Addiction

项目3中提出的实验将扩展人类受试者的神经成像研究（项目1， 博士Breiter）和啮齿类动物（项目2，Marota博士）研究细胞机制， 疼痛和阿片类药物成瘾之间的相互作用。许多研究表明，中央 多巴胺能系统对奖赏、记忆形成和滥用药物成瘾至关重要。同样地， 多巴胺能系统已显示在疼痛和疼痛调节中起重要作用。电流 数据还表明，大脑区域，如脑桥核（NAc），可能接受来自 伤害感受和阿片类药物的作用。在这个项目中，以及在项目2中， 条件性位置偏爱（mCPP）和后爪单关节炎将用于模拟阿片类药物成瘾 和慢性疼痛。 我们假设中脑边缘脑区多巴胺受体（DR）的激活，如NAc， 与mCPP和后爪单关节炎相关的蛋白质表达将有助于mCPP和 疼痛行为，这将通过NAc内的多巴胺能和多巴胺能相互作用调节， cAMP/PKA/CREB通路 和丝裂原活化蛋白激酶（MAPK）。这一主要假设将使用 药理学工具、免疫组织化学、Western印迹、实时RT-PCR、ELISA和蛋白激酶 活性测定，以实现三个具体目标：（1）检查mCPP之间的行为相互作用 （2）探讨脑DR在mCPP与疼痛相互作用中的作用 （3）探讨DR介导的mCPP与mCPP相互作用的细胞机制。 疼痛行为 结合项目1和项目2获得的数据，我们预计该项目将提供新的 关于疼痛和阿片类药物成瘾在细胞和分子水平上相互作用的信息。

The experiments proposed in project 3 will extend the neuroimaging studies of human subjects (Project 1, Dr. Breiter) and rodents (Project 2, Dr. Marota) to examine the cellular mechanisms underlying the interaction between pain and opioid addiction. Many studies have demonstrated that the central dopaminergic system is critical to rewarding, memory formation, and addiction to drugs of abuse. Similarly, the dopaminergic system has been shown to play a significant role in pain and pain modulation. Current data also suggest that brain regions such as nucleus accumbens (NAc) may receive converging inputs from both nociception and the opioid effects. In this project, as well as in project 2, a rat model of morphine conditioned place preference (mCPP) and of hindpaw monoarthritis will be used to mimic opioid addiction and chronic pain, respectively. We hypothesize that activation of dopamine receptors (DR) within mesolimbic brain regions such as NAc associated with mCPP and hindpaw monoarthritis would contribute to the interaction between mCPP and pain behaviors, which would be regulated by the glutamatergic and dopaminergic interaction within NAc via the cyclic AMP (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway and mitogen-activated protein kinases (MAPK). This main hypothesis will be examined using pharmacological tools, immunohistochemistry, Western blot, real-time RT-PCR, ELISA, and protein kinase activity assay to accomplish three specific aims: (1) To examine the behavioral interaction between mCPP and hindpaw monoarthritis; (2) To investigate the role of brain DR in the interaction between mCPP and pain behaviors; and (3) To explore the DR-mediated cellualr mechanisms of the interaction between mCPP and pain behaviors. Together with the data obtained from project 1 and project 2, we expect that this project will provide novel information regarding the interaction between pain and opioid addiction at the cellular and molecular level.