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

疼痛和奖励被认为是对立的过程，但在重叠的大脑结构中进行处理。它 已经证明，奖励刺激可以降低疼痛敏感性，而疼痛可以削弱奖励 导致快感缺失的过程。然而，目前还不知道疼痛的存在如何改变 加强自然奖励和阿片类药物的特性。中脑边缘通路是重要的脑核团， 阿片类药物成瘾的改变使其成为研究阿片类药物滥用机制基础的理想神经回路 在痛苦面前。阿片类药物诱导中脑中脑腹外侧核多巴胺释放的研究 有助于他们的滥用潜力，其中奖励信号的非稳态转变导致病理状态 上瘾的人Mu阿片受体（MOPR）激动剂是积极的加强，并仍然是主要的 用于临床和娱乐滥用的阿片类药物。相反，大脑κ阿片样物质的激活 受体（KOPR）通过抑制核内的中脑边缘DA和5-HT活性而引起烦躁不安 NAc奖励电路。据认为，这两个对立的阿片受体系统共同作用， 维持情感状态的平衡，然而一个或另一个系统的失调可能导致戏剧性的 奖励处理行为的变化。我们最近报道，持续性炎症性疼痛 影响腹侧被盖区（VTA）中MOPR的功能，伴随着μ-阿片诱导的 NAc中的DA释放可能是观察到的非常高剂量的 阿片类药物有趣的是，我们的初步研究结果表明，持续的炎症性疼痛增强KOPR功能， 在NAc中，促进负面情绪状态（即整体动机状态下降， 厌恶行为），这可能是在高剂量时驱动阿片类药物消耗增加的关键 最近提出的维持药物寻求和摄入量增加的建议。综上所述各项 初步研究结果强烈支持这一多学科建议的中心假设，即疼痛可以减少 通过增强强啡肽-KOPR系统，VTA-NAc多巴胺奖赏回路的活性 活动，以减少动机和促进烦躁不安。我们假设这种疼痛诱导的KOPR介导的 消极的情感状态驱使高剂量阿片类药物的摄入，导致滥用和药物递增。使用 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，我们建议确定是否在体内 在VTA-NAc回路中操纵强啡肽-KOPR系统可以防止疼痛引起的负面影响， 导致阿片类药物剂量增加

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.