Cortical opioid dysfunction in chronic pain

 描述（由申请人提供）：慢性疼痛与急性伤害性疼痛在其潜在机制、症状，特别是对治疗的反应方面有根本不同。慢性疼痛与焦虑和抑郁等疾病的共病率很高。一些研究表明，在慢性疼痛期间，疼痛的情感/情绪特征变得更加主导。重要的是，目前的镇痛治疗取得积极的临床结果似乎与疼痛慢性化呈负相关。对慢性疼痛患者的神经影像学研究已经确定了阿片和多巴胺功能改变的大脑区域，这表明这些神经递质系统的损伤可能是从急性疼痛向慢性疼痛转变的基础。我们最近在动物疼痛模型中证明，持续疼痛的缓解是有益的，需要多巴胺信号在丘脑核（NAc）。此外，这些疼痛缓解的行为和神经化学措施依赖于扣带皮层（ACC）中的内源性阿片样物质神经传递，这是一个编码疼痛厌恶的区域。慢性疼痛可能在ACC中产生持续的阿片样物质信号传导，导致该区域阿片样物质递质-受体功能的进行性变化，并且随着时间的推移，镇痛效果降低。确定人类疼痛、脑神经元适应不良和疼痛治疗的镇痛效果之间是否存在因果关系是困难的，而且可能是不道德的。因此，我们将采用慢性神经性疼痛的大鼠模型进行为期六个月的纵向研究，以更接近地模拟人类慢性疼痛状况。在目标1中，我们将研究阿片和多巴胺神经传递的大脑区域编码的情感和动机方面的疼痛的时间变化。我们将使用快速扫描循环伏安法（FSCV）和快速扫描控制吸附伏安法（FSCAV）技术在我们的实验室中开创，允许测量的相位和紧张水平的多巴胺在清醒的行为动物前所未有的时间和空间分辨率。多巴胺的阶段性释放可能受到慢性疼痛相关的紧张性多巴胺水平变化的影响。此外，我们将使用一种新的体内微透析方法，包括在线保存与LC-MS 3检测相结合，以测量控制和疼痛条件下行为动物ACC中内源性阿片肽的低水平。目的2将研究疼痛慢性化是否与阿片和多巴胺信号传导的疗效降低有关。我们的实验室证明，在动物中，疼痛厌恶的缓解产生负强化，可以使用条件位置偏好（CPP）进行行为评估。CPP可以被视为动物的镇痛功效的“自我报告”，其包括学习以及持续疼痛的动机和情感特征，因此提供了可能与人类疼痛体验翻译相关的信息。我们将使用CPP范式评价持续性神经性疼痛的进展，并评估阿片类和非阿片类镇痛药随时间推移的疗效。目标3将确定是否可以通过使用目前临床试验中的方法逆转慢性疼痛来实现多巴胺和阿片功能的正常化。拟议的研究解决了我们知识中的空白，包括与疼痛相关的大脑多巴胺和阿片功能的因果关系，慢性和可逆性。此外，这些研究可能允许客观量化慢性病，并作为有效缓解疼痛治疗的生物标志物，可以加速新疼痛治疗方法的转化和发现。

 DESCRIPTION (provided by applicant): Chronic pain is fundamentally different from acute nociceptive pain in its underlying mechanisms, symptoms and especially, in response to treatment. There is a high comorbidity of chronic pain with diseases such as anxiety and depression. Some studies suggest that during chronification of pain, the affective/emotional features of pain become more dominant. Critically, achieving a positive clinical outcome with current analgesic therapies appears to be negatively correlated with pain chronicity. Neuroimaging studies in chronic pain patients have identified brain regions with altered opioid and dopamine function, suggesting that impairments in these neurotransmitter systems could underlie the transition from acute to chronic pain. We have recently demonstrated in animal pain models that relief of ongoing pain is rewarding and requires dopamine signaling in the nucleus accumbens (NAc). Moreover, these behavioral and neurochemical measures of pain relief depend on endogenous opioid neurotransmission in the cingulate cortex (ACC), an area encoding aversiveness of pain. Chronic pain may produce sustained opioid signaling in the ACC resulting in progressive changes in opioid transmitter-receptor function in this region, and over time, in reduced analgesic efficacy. Determining whether there is a causal relationship between pain, brain neuronal maladaptations and analgesic effectiveness of pain therapies in humans is difficult and potentially unethical. Therefore, we will employ a rat model of chronic neuropathic pain to perform longitudinal studies over a six months period to more closely mimic the human chronic pain condition. In Aim 1 we will investigate the temporal changes in opioid and dopamine neurotransmission in the brain regions encoding affective and motivational aspects of pain. We will use fast scan cyclic voltammetry (FSCV) and fast scan controlled adsorption voltammetry (FSCAV) techniques pioneered in our laboratories that allow measurements of phasic and tonic levels of dopamine in awake behaving animals with unprecedented temporal and spatial resolution. The phasic release of dopamine may be influenced by chronic pain-related changes in tonic dopamine levels. Additionally, we will use a novel in vivo microdialysis method involving online preservation coupled with LC-MS3 detection to measure the low levels of endogenous opioid peptides in the ACC in behaving animals in control and pain conditions. Aim 2 will investigate whether pain chronicity is related to reduced efficacy of opioid and dopamine signaling. Our laboratory demonstrated that in animals, relief of pain aversiveness produces negative reinforcement that can be assessed behaviorally using conditioned place preference (CPP). CPP can be viewed as the animal's "self- report" of analgesic efficacy that encompasses learning as well as motivational and affective features of ongoing pain and therefore provides information that is likely of translational relevance to the human pain experience. We will use the CPP paradigm to evaluate progression of ongoing neuropathic pain and to assess the efficacy of opioid and non-opioid analgesics over time. Aim 3 will establish if normalization of dopamine and opioid function can be achieved with reversal of chronic pain using methods currently in clinical trials. The proposed studies address gaps in our knowledge that include causality, chronicity and reversibility of pain- related brain dopamine and opioid function. Additionally, these studies may allow for objective quantification of chronicity and serv as a biomarker of effective pain relieving treatments that may speed translation and discovery of new pain therapeutics.