Defining a role for kappa opioid system in affective behavior and drug escalation in pain

痛苦和回报被认为是对立的过程，但它们是在重叠的大脑结构中处理的。它 已经证明，奖励刺激可以降低疼痛敏感度，而疼痛会削弱奖励 导致非享乐主义状态的处理。然而，目前尚不清楚疼痛的存在如何改变 增强自然奖赏和阿片类药物的特性。中脑边缘通路是一种关键的脑核，即 改变阿片成瘾，使其成为研究阿片滥用机制基础的理想神经回路 在痛苦的存在下。阿片类药物诱导伏隔核多巴胺(DA)的释放 导致它们的滥用潜力，其中奖励信号的变态变化导致病理状态 上瘾的人。MU阿片受体(MOPR)激动剂正在积极增强，并仍占主导地位 用于临床和娱乐滥用目的的阿片类药物。相比之下，脑内kappa阿片类药物的激活 受体(KOPR)通过抑制中脑边缘多巴胺和5-羟色胺在核内的活性而引起烦躁不安 南汽奖励电路。据认为，这两个相反的阿片受体系统共同作用，部分地 保持情感状态的平衡，然而其中一个系统的失调可能会导致戏剧性的 奖赏处理行为的变化。我们最近报道了持续性炎性疼痛的负面影响 MOPR对腹侧被盖区(VTA)功能的影响，并伴随着Mu阿片类药物诱导的丧失 NAC中DA的释放，这可能是观察到的极高剂量海洛因摄入量增加的部分原因 阿片类药物。有趣的是，我们的初步发现表明，持续性炎症性疼痛增强了KOPR功能 在NAC中，促进负面情绪状态(即总体动机状态的减少和增强 厌恶行为)，这可能是导致大剂量阿片类药物消费增加的关键原因 是可获得的，正如最近提议的那样，以维持寻求毒品和增加摄入量。这些加在一起， 初步发现有力地支持了这一多学科建议的中心假设，即疼痛减轻 通过增强强啡肽-KOPR系统激活VTA-NAC多巴胺奖赏回路 减少动机和促进烦躁不安的活动。我们假设这种疼痛诱导的KOPR介导 消极的情感状态会导致大剂量阿片类药物的摄入，导致滥用和药物升级。使用 一系列多学科方法，包括电生理学、微透析、伏安法、光遗传学、 化学遗传学、小鼠遗传学和啮齿动物PET成像工具，我们建议确定在体内 在VTA-NAC回路中操纵强啡肽-KOPR系统可防止疼痛引起的负面影响， 导致阿片类药物剂量上升。

Pain and reward are considered opponent processes but are processed within overlapping brain structures. It has been demonstrated that rewarding stimuli can decrease pain sensitivity, whereas pain can impair reward processing leading to an anhedonic state. However, it is not yet known how the presence of pain modifies the reinforcing properties of natural rewards and opioids. The mesolimbic pathway is a critical brain nuclei that is altered in opioid addiction making it an ideal neural circuit to investigate the mechanistic basis for opioid abuse in the presence of pain. Opioid-induced released of dopamine (DA) in the nucleus accumbens (NAc) contributes to their abuse potential, where an allostatic shift in reward signaling leads to the pathological state of addiction. Mu opioid receptor (MOPR) agonists are positively reinforcing and remain the predominant opioids used for clinical and recreational-abuse purposes. In contrast, the activation of brain kappa opioid receptors (KOPR) causes dysphoria via suppression of mesolimbic DA and 5HT activity within the nucleus NAc reward circuitry. It is thought that these two opposing opioid-receptor systems work together to partially maintain the balance of affective state, however dysregulation of one or the other system can lead to dramatic changes in reward processing behaviors. We recently reported that persistent inflammatory pain negatively impacts function of MOPR in the ventral tegmental area (VTA) with a concomitant loss of mu-opioid-induced DA release in the NAc which may partially underlie the observed increase in the intake of very high doses of the opioid. Interestingly, our initial findings indicate that persistent inflammatory pain enhances KOPR function in the NAc, promoting negative affect states (i.e. decrease in the overall motivational state and enhanced aversive behavior) which may be crucially involved in driving increased opioid consumption when high doses are accessible, as recently proposed to maintain drug seeking and escalation of intake. Taken together, these preliminary findings strongly support the central hypothesis of this multidisplinary proposal that pain reduces the activity of the VTA-NAc dopamine reward circuit, via an enhancement of the dynorphin-KOPR system activity to decrease motivation and promote dysphoria. We hypothesize that this pain-induced KOPR-mediated negative affective state drives the intake of high dose opioids leading to misuse and drug escalation. Using a series of multidisplinary approaches including electrophysiology, microdialysis, voltammetry, optogenetics, chemogenetics, mouse genetics, and rodent PET imaging tools, we propose to determine whether in vivo manipulation of dynorphin-KOPR system in the VTA-NAc circuit prevents pain-induced negative affect which drives opioid dose escalation.