Cortical opioid dysfunction in chronic pain

 描述(申请人提供)：慢性疼痛从根本上不同于急性伤害性疼痛的潜在机制，症状，特别是对治疗的反应。慢性疼痛与焦虑和抑郁等疾病的共患率很高。一些研究表明，在疼痛的慢性化过程中，疼痛的情感/情绪特征变得更加主导。关键的是，目前的止痛治疗取得了积极的临床结果，似乎与疼痛的慢性化呈负相关。慢性疼痛患者的神经成像研究发现，阿片类药物和多巴胺功能改变的大脑区域，表明这些神经递质系统的损害可能是从急性疼痛过渡到慢性疼痛的基础。我们最近在动物疼痛模型中证明，缓解持续的疼痛是有回报的，需要伏核(NAC)中的多巴胺信号。此外，这些缓解疼痛的行为和神经化学措施依赖于内源性阿片类药物在扣带回皮质(ACC)的神经传递，扣带回皮质是编码疼痛厌恶的区域。慢性疼痛可能在ACC产生持续的阿片信号，导致该区域阿片递质-受体功能的进行性变化，并随着时间的推移而降低止痛效果。确定疼痛、脑神经元适应不良和人类疼痛疗法的止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，我们将使用慢性神经病理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的慢性疼痛状况。在目标1中，我们将研究阿片类药物和多巴胺神经传递在编码疼痛的情感和动机方面的大脑区域的时间变化。我们将使用我们实验室首创的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，以前所未有的时间和空间分辨率测量清醒行为动物的多巴胺相和紧张性水平。多巴胺的时相释放可能受慢性疼痛相关的强直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，包括在线保存和LC-MS3检测，以测量在控制和疼痛条件下行为动物的ACC中低水平的内源性阿片肽。目的2将研究疼痛慢性化是否与阿片类药物和多巴胺信号转导效果降低有关。我们的实验室证明，在动物身上，疼痛厌恶的缓解会产生负强化，这可以用条件化位置偏爱(CPP)来评估。CPP可被视为动物对止痛效果的“自我报告”，包括持续疼痛的学习以及动机和情感特征，因此提供的信息可能与人类疼痛体验具有翻译相关性。我们将使用CPP范式来评估持续神经病理性疼痛的进展，并评估阿片类和非阿片类镇痛剂随时间的疗效。目的3将确定是否可以通过使用目前处于临床试验中的方法逆转慢性疼痛来实现多巴胺和阿片类药物功能的正常化。拟议的研究解决了我们知识中的空白，包括疼痛相关脑多巴胺和阿片功能的因果关系、慢性性和可逆性。此外，这些研究可能允许客观量化慢性和Serv作为有效缓解疼痛治疗的生物标记物，这可能会加速新疼痛疗法的转换和发现。

 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.