Cortical opioid dysfunction in chronic pain

慢性疼痛中的皮质阿片类药物功能障碍

基本信息

批准号：
9479906
负责人：
Frank Porreca
金额：
$ 0.84万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9479906
关键词：
Ablation Acute Acute Pain Address Adsorption Affective Affective Symptoms Analgesics Anatomy Animal Model Animals Anxiety Area Behavior Behavioral Binding Binding Proteins Biological Markers Biological Preservation Brain Brain region Characteristics Chronic Clinical Clinical Trials Comorbidity Coupled Cytotoxin Decision Making Detection Development Disease Dopamine Drug usage Effectiveness Emotional Etiology Functional disorder GTP-Binding Proteins Human Impairment Injury Investigation Knowledge Laboratories Lead Learning Link Longitudinal Studies Measurement Measures Mental Depression Messenger RNA Methods Microdialysis Modeling Modification Morphine Motivation Negative Reinforcements Neurons Neuropeptides Neurotransmitters Nociception Nucleus Accumbens Opioid Opioid Analgesics Opioid Peptide Opioid Receptor Outcome Output Pain Pain management Patient Self-Report Patients Periodicity Phase Positron-Emission Tomography Predisposition Rattus Recovery Reporting Resiniferatoxin Resolution Rewards Role Scanning Signal Transduction Speed Substance P Substance P Receptor Substance administration Symptoms System Techniques Therapeutic Time Translations Ventral Striatum animal pain associated symptom awake chronic neuropathic pain chronic pain cingulate cortex depressive behavior depressive symptoms desensitization emotional symptom endogenous opioids experience gabapentin hedonic in vivo neurochemistry neuroimaging neurotransmission novel painful neuropathy pre-clinical preference protein expression public health relevance radioligand radiotracer receptor receptor function response success treatment response

项目摘要

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.

描述（由申请人提供）：慢性疼痛在其根本机制、症状以及对治疗的反应方面与急性伤害性疼痛有根本不同。一些研究表明，慢性疼痛与焦虑和抑郁等疾病有很高的共存率。在疼痛慢性化过程中，疼痛的情感/情绪特征变得更加重要，目前的镇痛疗法取得积极的临床结果似乎与慢性疼痛的神经影像学研究呈负相关。疼痛患者已经发现阿片类药物和多巴胺功能发生改变的大脑区域，这表明这些神经递质系统的损伤可能是从急性疼痛转变为慢性疼痛的基础。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，并且需要多巴胺信号传导。此外，这些缓解疼痛的行为和神经化学措施依赖于扣带皮层（ACC）中的内源性阿片类药物神经传递，该区域编码慢性疼痛，可能会产生持续的阿片类药物信号。 ACC 导致该区域阿片类药物递质受体功能的逐渐变化，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镇痛效果之间是否存在因果关系是困难且困难的。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) 技术来测量疼痛的相位和紧张水平。清醒行为动物中的多巴胺具有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强直性多巴胺水平变化的影响。我们将使用一种新型体内微透析方法在线保存并结合 LC-MS3 检测来测量对照和疼痛条件下行为动物 ACC 中内源性阿片肽的低水平，目标 2 将研究疼痛慢性是否与功效降低有关。我们的实验室证明，在动物中，疼痛厌恶的缓解会产生负面行为强化，可以使用条件性位置偏好（CPP）来评估，这可以被视为动物的“自我”。镇痛功效报告”，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相关的信息。我们将使用 CPP 范式来评估持续神经性疼痛的进展并评估目标 3 将确定阿片类药物和非阿片类药物镇痛药的疗效是否可以通过目前临床试验中的方法逆转慢性疼痛来实现。我们的知识包括与疼痛相关的大脑多巴胺和阿片类药物功能的因果关系、慢性性和可逆性。此外，这些研究可能允许对慢性性进行客观量化，并作为有效缓解疼痛治疗的生物标志物，从而加速新疼痛疗法的转化和发现。。