Neurobiology and Treatment of Pain

描述（由申请人提供）：这是一份竞争性续期申请，旨在继续我们在疼痛相关行为抑郁症的表达、神经生物学和治疗方面的临床前研究。疼痛是一项重要的临床挑战，通常与临床相关的行为和情绪抑郁有关。此外，缓解与疼痛有关的抑郁症是人类和兽医学治疗的共同目标。我们的研究基于这样一个命题，即对疼痛相关抑郁的研究可以为疼痛情感维度的调节机制和疼痛治疗的新策略提供新的基础科学见解。到目前为止，我们的数据表明，在伏核（NAc）和前额叶皮质（PFC）中，失调的中皮质边缘多巴胺（DA）信号在疼痛抑制行为中起中介作用，本应用程序提出的研究将寻求与该机制相关的假设。具体来说，在目前的项目期间，我们开发并验证了一种新的大鼠急性和慢性疼痛抑制行为的行为分析。然后，我们使用该程序来实现以下研究目标：(1)从多个药物类别中评估bbbb40种药物，以确认我们的程序对已知镇痛药的敏感性和对镇痛药与非镇痛药的选择性；(2) NAc疼痛性行为抑郁与DA释放疼痛性抑郁的相关性；(3)发现疼痛状态也会增加脑源性神经营养因子的PFC表达，这是一种与非疼痛应激源引起的抑郁有关的蛋白质。在这个竞争性的更新申请中，我们建议在一系列三个具体目标中扩展这项工作。目的1将在疼痛抑制行为的行为分析中检验DA激动剂会补偿疼痛效应并产生镇痛的假设。我们建议在急性和慢性疼痛抑制行为的检测中评估D1， D2和D3 DA受体激动剂的镇痛作用。我们的假设预测一种或多种DA受体亚型的激动剂将有效。间接DA激动剂的作用也将进行比较。目的2将验证疼痛状态调节NAc和PFC中DA信号下游介质的假设。我们建议评估疼痛对PFC DA释放的影响，以补充我们在NAc中的微透析研究。此外，我们建议通过评估(a) DA转运体和D1， D2和D3受体的密度，以及(b)两个互补的和生理相关的DA音调指标（FosB和蛋白激酶b的磷酸化）的表达来测试疼痛改变的DA释放的后果。我们预测疼痛相关的DA减少会引起代偿性变化。目的3将验证疼痛状态也会调节NAc和pfc中BDNF介导的信号传导的假设。中皮质边缘系统中BDNF表达的增加与抑郁行为的发展有关。我们预测疼痛状态将增强BDNF信号，并且在该系统中通过病毒载体直接过度表达或敲低BDNF信号将调节疼痛抑制行为的表达。

DESCRIPTION (provided by applicant): This is a competing renewal application to continue our preclinical research on expression, neurobiology and treatment of pain-related behavioral depression. Pain is a significant clinical challenge that is often associated with clinically relevnt depression of behavior and mood. Moreover, relief of pain-related depression is a common goal of treatment in both human and veterinary medicine. Our research is founded on the proposition that research on pain-related depression could provide new basic-science insights on mechanisms that mediate affective dimensions of pain and new strategies for pain treatment. Our data so far suggest a role for dysregulated mesocorticolimbic dopamine (DA) signaling in nucleus accumbens (NAc) and prefrontal cortex (PFC) as a mediator of pain-depressed behavior, and studies proposed in this application would pursue hypotheses related to this mechanism. Specifically, during the current project period, we developed and validated a new behavioral assay of acute and chronic pain-depressed behavior in rats. We then used this procedure to achieve the following research goals: (1) evaluation of >40 drugs from multiple drug classes to confirm that our procedure is both sensitive to known analgesics and selective for analgesics vs. non- analgesics; (2) correlation of pain-related depression of behavior and pain-related depression of DA release in NAc; and (3) discovery that pain states also increase PFC expression of brain-derived neurotrophic factor, a protein implicated in depression consequent to non-pain stressors. In this competing renewal application, we propose to extend on this work in a series of three specific aims. Aim 1 will test the hypothesis that DA agonists wil compensate for pain effects and produce analgesia in behavioral assays of pain- depressed behavior. We propose to evaluate analgesic effects of D1, D2 and D3 DA receptor agonists in assays of acute and chronic pain-depressed behavior. Our hypothesis predicts that agonists at one or more DA receptor subtype will be effective. Effects of indirect DA agonists will also be examined for comparison. Aim 2 will test the hypothesis that pain states modulate downstream mediators of DA signaling in NAc and PFC. We propose to assess pain effects on PFC DA release to complement our microdialysis studies in NAc. In addition, we propose to test consequences of pain-altered DA release by evaluating (a) density of the DA transporter and of D1, D2 and D3 receptors, and (b) expression of two complementary and physiologically relevant indicators of DA tone ( FosB and phosphorylation of protein kinase B). We predict compensatory changes in response to pain-related decreases in DA. Aim 3 will test the hypothesis that pain states will also modulate signaling mediated by BDNF in NAc and PFC. Increased expression of BDNF within the mesocorticolimbic system has been implicated in the development of depressive behavior. We predict that pain states will augment BDNF signaling, and that direct overexpression or knockdown of BDNF signaling within this system with viral vectors will modulate expression of pain-depressed behavior.