Neurobiology and Treatment of Pain

描述(由申请人提供)：这是一个竞争性的续签申请，以继续我们关于疼痛相关行为抑郁的表达、神经生物学和治疗的临床前研究。疼痛是一项重大的临床挑战，通常与临床上相关的行为和情绪抑郁有关。此外，缓解疼痛相关的抑郁是人类和兽医治疗的共同目标。我们的研究建立在这样一个命题上，即对疼痛相关抑郁的研究可以为调节疼痛情感维度的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，伏核(NAC)和前额叶皮质(PFC)中调节失调的中皮质边缘多巴胺(DA)信号作为疼痛抑郁行为的中介，本申请中提出的研究将进一步探讨与此机制相关的假说。具体地说，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郁行为的行为测试。然后，我们使用这一程序来实现以下研究目标：(1)对来自多个药物类别的40种药物进行评估，以确认我们的程序既对已知的镇痛剂敏感，也对镇痛剂和非镇痛剂具有选择性；(2)疼痛相关的行为抑郁与NAC中DA释放的疼痛相关抑制的相关性；以及(3)发现疼痛状态也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导致的抑郁有关的蛋白质。在这个相互竞争的续签申请中，我们建议在这项工作上扩展一系列三个具体目标。目的1将在疼痛抑制行为的行为学分析中验证DA激动剂将补偿疼痛效应并产生止痛的假设。我们建议在急性和慢性疼痛抑制行为的测试中评估D_1、D_2和D_3DA受体激动剂的止痛效果。我们的假设预测，一个或多个DA受体亚型的激动剂将是有效的。还将检查间接DA激动剂的效果以进行比较。目的2验证疼痛状态调节NAC和PFC中DA信号下游介体的假说。我们建议评估疼痛对PFC DA释放的影响，以补充我们在NAC进行的微透析研究。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)两个互补的和生理上相关的DA张力指标(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。我们预测在疼痛相关的DA减少时会发生代偿性变化。目标3将测试这一假设，即疼痛状态也将调制NAC和PFC中由BDNF介导的信号。脑源性神经营养因子在中皮质边缘系统中的表达增加与抑郁行为的发生有关。我们预测疼痛状态将增强BDNF信号，而病毒载体在该系统中直接过表达或敲除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.