Cellular, synaptic, and network adaptations of MCL addiction and motivation circuits (NAc, VTA, PAG) with chronic pain and opioid exposure

慢性疼痛是美国最大的残疾来源，通常用阿片类药物治疗。许多慢性疼痛患者 给予处方阿片类药物治疗与成瘾作斗争阿片类药物滥用已成流行病 在美国，慢性疼痛和阿片类药物滥用之间联系的神经生物学基础是 不确定。然而，最近的研究表明，慢性疼痛是由相同的中脑边缘环路决定的 吸毒成瘾。腹侧被盖区(VTA)和伏隔核(NAC)似乎是这一区域的重要中枢。 电路。他们在吸毒成瘾中的作用是公认的。新的是，它们在慢性疼痛中也扮演着关键角色。我们 在慢性疼痛的啮齿动物备用神经损伤(SNI)模型中，存在细胞特异性和区域特异性 NAC中的适应，包括固有的和突触的变化。这些变化与疼痛有因果关系。 VTA内多巴胺能神经元的行为和活动变化。尽管阿片类药物有明显的影响 在VTA和NAC上，阿片类药物如何影响SNI诱导的NAC适应是完全未知的。此外，它是 不清楚慢性疼痛如何改变阿片类药物的成瘾潜力。在项目2中，我们的总体目标是填补这些 我们在理解上的差距。为此，一系列现代行为、解剖学、生理学和分子生物学 将在小鼠模型中使用方法来实现四个特定目标：特定目标1：确定吗啡 接受自我注射吗啡训练的SNI小鼠的强化和寻找行为得到增强。我们的工作假说 是SNI会增加吗啡和寻药行为的强化效果。具体目标2：确定 SNI是否对支配NAC内侧壳和核的VTA DA神经元有不同影响，以及这些神经元是否 效应受吗啡自身给药(MSA)的调节。我们的工作模式是VTA区域支配着 MSNAc和中航是不重叠的，它们对SNI的反应方式基本上是相反的。此外，我们假设 短期的MSA将减弱SNI诱导的适应。具体目标3：确定短期(5d)吗啡 自我给药改变特定NAC回路中SNI诱导的适应。我们的工作假设是MSA很快 SNI后将抑制上行的伤害性信号和减弱VTA活动的改变，导致仅 MsNAc/CNAC电路的适度适应。具体目标4：确定长期(14天)吗啡自身 给药和戒断改变了SNI在特定NAC回路中诱导的适应。我们的工作假设是 随着时间的推移，吗啡对VTA和NAC回路的有益作用将减弱，导致SNI诱发的增强 NAC回路中的适应，导致吗啡奖励和药物寻找的增强。为这四项研究概述的研究 AIMS应该为慢性疼痛增加潜在的 对阿片类药物上瘾，如吗啡，这样做表明有新的治疗方法。此外，这些目标是对以下目标的补充 项目1、3和4，创造了协同的机会。

Chronic pain is the top source of disability in the U.S. and is commonly treated with opiates. Many chronic pain patients given prescription opiates for treatment struggle with addiction and the abuse of opioids has reached epidemic proportions in the U.S. The neurobiological basis for the connection between chronic pain and opioid abuse is uncertain. However, recent work has shown that chronic pain is shaped by the same mesolimbic circuitry underlying drug addiction. The ventral tegmental area (VTA) and nucleus accumbens (NAc) appears to be critical hubs of this circuitry. Their role in drug addiction is well-established. What is new is that they also play key roles in chronic pain. We have shown that in the rodent spared nerve injury (SNI) model of chronic pain there are cell-specific and region-specific adaptations in the NAc that include both intrinsic and synaptic changes. These changes were causally linked to pain behavior and alterations in the activity of dopaminergic neurons in the VTA. Although there are clear effects of opioids on the VTA and NAc, how opioids shape SNI-induced adaptations in the NAc is completely unexplored. Moreover, it is unclear how chronic pain modifies the addictive potential of opioids. In Project 2, our over-arching goal is to fill these gaps in our understanding. To this end, an array of modern behavioral, anatomical, physiological and molecular approaches will be used in mouse models to achieve four specific aims: Specific Aim 1: To determine whether morphine reinforcement and seeking behavior is enhanced in SNI mice trained to self-administer morphine. Our working hypothesis is that SNI will increase the reinforcing efficacy of morphine and drug seeking behavior. Specific Aim 2: To determine whether SNI differentially affects VTA DA neurons innervating the medial shell and core of the NAc and whether these effects are modulated by morphine self-administration (MSA). Our working model is that VTA regions innervating the msNAc and cNAc are non-overlapping and respond in largely opposing ways to SNI. Moreover, we hypothesize that short-term MSA will diminish SNI-induced adaptations. Specific Aim 3: To determine whether short-term (5d) morphine self-administration alters SNI-induced adaptations in specific NAc circuits. Our working hypothesis is that MSA shortly after SNI will dampen ascending nociceptive signaling and attenuate alterations in the activity of VTA, resulting in only modest adaptations in msNAc/cNAc circuits. Specific Aim 4: To determine whether long-term (14 d) morphine self- administration and withdrawal alters SNI induced adaptations in specific NAc circuits. Our working hypothesis is that with time the beneficial effects of morphine on VTA and NAc circuits will wane, leading to augmentation of SNI-induced adaptations in NAc circuits, resulting in enhanced morphine reward and drug seeking. The studies outlined for these four aims should provide fundamental new insights into the mechanisms by which chronic pain increases the potential for addiction to opioids, like morphine, and in so doing point to novel therapies. Moreover, these aims complement those of Projects 1, 3 and 4, creating an opportunity for synergy.