Neurobiology and Treatment of Pain

神经生物学和疼痛治疗

• 批准号: 9317540
• 负责人: Sidney S Negus
• 金额: $ 33.6万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317540
• 关键词: Absence of pain sensation; Acids; Acute; Acute Pain; Affective; Agonist; Analgesics; Animal Model; Area; Basic Science; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain-Derived Neurotrophic Factor; Clinical; Complement; Data; Depressed mood; Development; Dimensions; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine Receptor; Dopamine Uptake Inhibitors; Electrical Stimulation of the Brain; Endocannabinoids; Evaluation; Flupenthixol; Funding; Gene Expression; Glutamate Receptor; Goals; Health; Human; Intraperitoneal Injections; Ligands; Literature; Measures; Mediating; Mediator of activation protein; Mental Depression; Metabolism; Microdialysis; Molecular; Moods; Morphine; N-Methylaspartate; Neurobiology; Nicotinic Receptors; Non-Steroidal Anti-Inflammatory Agents; Norepinephrine; Nucleus Accumbens; Pain; Pain management; Pharmaceutical Preparations; Phosphorylation; Physiological; Prefrontal Cortex; Procedures; Proteins; Proto-Oncogene Proteins c-akt; Publishing; RTI-113; Rattus; Research; Rewards; Role; Self Stimulation; Series; Serotonin; Signal Pathway; Signal Transduction; Signaling Protein; Source; Stimulus; System; Testing; Ventral Tegmental Area; Veterinary Medicine; Viral Vector; Visceral pain; Work; base; behavioral study; cannabinoid receptor; chronic depression; chronic pain; clinical efficacy; clinically relevant; delta opioid receptor; density; depressive behavior; dopamine D3 receptor; dopamine system; dopamine transporter; dopaminergic neuron; improved; inhibitor/antagonist; insight; kappa opioid receptors; knock-down; monoamine; mood regulation; motivated behavior; mu opioid receptors; neurochemistry; overexpression; pre-clinical research; protein expression; public health relevance; receptor; response; social; stressor; treatment effect; uptake

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.

描述（由申请人提供）：这是一个竞争性的更新申请，以继续我们对疼痛相关行为抑郁症的表达，神经生物学和治疗的临床前研究。疼痛是一个重要的临床挑战，通常与临床相关的行为和情绪抑郁有关。此外，缓解疼痛相关的抑郁症是人类和兽医学治疗的共同目标。我们的研究建立在这样的假设之上：对疼痛相关抑郁症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，调节异常的中脑皮质边缘多巴胺（DA）信号传导的作用，在神经核（NAc）和前额叶皮层（PFC）作为介质的疼痛抑郁行为，并在本申请中提出的研究将追求与此机制相关的假设。具体来说，在当前项目期间，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定。然后，我们使用该程序来实现以下研究目标：（1）评估来自多个药物类别的>40种药物，以确认我们的程序对已知的镇痛剂敏感并且对镇痛剂相对于非镇痛剂具有选择性;（2）NAc中疼痛相关的行为抑制和疼痛相关的DA释放抑制的相关性;以及（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，我们建议在一系列的三个具体目标中扩展这项工作。目的1将在疼痛-抑郁行为的行为测定中验证DA受体激动剂是否能补偿疼痛效应并产生镇痛作用的假设。我们建议在急性和慢性疼痛-抑郁行为试验中评价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是有效的。还将检查间接DA激动剂的作用以进行比较。目的2将测试的假设，疼痛状态调节下游介质的DA信号在NAc和PFC。我们建议评估疼痛对PFC DA释放的影响，以补充我们的微透析研究在NAc。此外，我们建议通过评估（a）DA转运蛋白和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DA释放的后果。我们预测的补偿性变化，在DA的疼痛相关的减少。目的3将测试的假设，疼痛状态也将调节由BDNF介导的信号在NAc和PFC。增加表达的BDNF中皮质边缘系统内已牵连在抑郁行为的发展。我们预测，疼痛状态将增加BDNF信号，并在该系统中直接过表达或敲除BDNF信号与病毒载体将调节表达的疼痛抑制行为。