Dissecting circuits mediating pain-induced alterations in motivated behavior

不适应疼痛导致的动力回路功能障碍可能是导致 自然和药物奖赏寻找行为的病理变化，但神经回路机制 这些影响在很大程度上是未知的。中脑边缘系统是整合疼痛和神经系统的关键网络节点。 奖励。多巴胺(DA)在中脑边缘系统通过VTA向NAC的传递早已被认识到 因为它在动机行为中扮演的角色。中脑边缘通路中DA信号的改变与 动机缺陷，疼痛中的动物表现出对自然和药物奖励的动机反应受损。 重要的是，从翻译的角度来看，疼痛与中脑边缘DA活性之间存在负相关。 人类经常被报道。MU阿片受体(MOPR)激动剂正在积极增强并保持 主要用于减轻临床疼痛和娱乐使用/滥用的阿片类药物。我们最近发现， 持续性炎性疼痛下调VTA中MOPR的功能，并伴随阿片类药物的丧失- 以剂量依赖的方式诱导NAC中DA的释放，导致更高剂量的 已知有助于滥用相关表型的阿片类药物。另外，我们的初步数据 提示持续性炎症导致内源性阿片类药物紧张增加，这可能导致 VTA中MOPR的脱敏作用。总而言之，这些发现表明疼痛抑制vtanac。 通过抑制中脑边缘多巴胺的释放实现神经回路活动。我们预测，这种影响是由 VTA内源性阿片张力增加和MOPR功能降低，对VTA产生负面影响 动物的动机状态导致了阿片类药物滥用相关的表型。在此应用程序中，我们 提出跨学科的前沿方法来剖析神经元和细胞机制 炎性疼痛时Mu阿片环路下调的潜在原因。在三个具体的方面 目的我们将：i)确定含Mu阿片类药物的GABA能环路下调的机制 炎性疼痛II)确定内源性Mu-阿片激动剂音调的增加是否改变Mu-阿片类药物 功能，以及这些过程是否对炎性疼痛的影响是必要和充分的 动机行为。最后，在第三个目标中，我们将直接可视化内源性阿片类药物所含神经元 在炎症性疼痛和动机状态下降的发展过程中的集合。在这里，我们将 确定mU-阿片受体，它们的内源性激动剂，在离散的中脑边缘神经回路中， 对于调节疼痛引起的阿片类药物摄取和动机行为的改变来说是必要的和充分的。

Maladaptive pain-induced dysfunction in motivational circuits are the likely critical factors that lead to pathological alterations in natural and drug reward seeking behaviors, yet the neural circuit mechanisms for these effects are largely unknown. The mesolimbic system is a key network node that integrates pain and reward. Dopamine (DA) transmission in the mesolimbic system, via the VTA to NAc has long been recognized for its role in motivated behavior. Alterations in DA signaling within the mesolimbic pathway are associated with motivational deficits, and animals in pain show impaired motivated responses to natural and drug reward. Importantly, from a translational perspective, negative correlations between pain and mesolimbic DA activity in humans have been often reported. Mu opioid receptor (MOPR) agonists are positively reinforcing and remain the predominant opioids used for alleviating clinical pain and recreational use/abuse. We recently found that persistent inflammatory pain downregulates function of MOPR in the VTA with a concomitant loss of opioid- induced DA release in the NAc in a dose-dependent manner leading to increase intake of higher doses of opioids which are known to contribute to abuse-associated phenotypes. In addition, our preliminary data suggest that persistent inflammation causes an increase in endogenous opioid tone which is likely leading to desensitization of MOPR in the VTA. Collectively, these findings suggest that pain suppresses VTANAc neural circuit activity through suppression of mesolimbic DA release. We predict that this effect is mediated by an increase in endogenous opioid tone and reduction of MOPR function in the VTA which negatively impact the animal's motivational state contributing to an opioid abuse-associated phenotype. In this application we propose cross disciplinary cutting-edge approaches to dissect the neuronal and cellular mechanisms underlying the downregulation of mu-opioid circuits in the presence of inflammatory pain. In three specific aims we will: i) determine the mechanisms for downregulation of mu-opioid-containing GABAergic circuits in inflammatory pain ii) determine whether increases in endogenous mu-opioid agonist tone changes mu-opioid function, and whether these processes are necessary and sufficient for the effects of inflammatory pain on motivated behavior. Finally, in a third aim we will directly visualize endogenous opioid-containing neuronal ensembles during the development of inflammatory pain and decreased motivational states. Here we will determine whether mu-opioid receptors, their endogenous agonists, within discrete mesolimbic neural circuits, are necessary and sufficient to mediate pain-induced alterations in opioid intake and motivated behavior.