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（由适用提供）：慢性疼痛从根本上与急性伤害性疼痛不同，其基本机制，症状，尤其是对治疗的响应。慢性疼痛与焦虑和抑郁等疾病的合并症很高。一些研究表明，在疼痛期间，疼痛的影响/情绪特征变得更加主导。至关重要的是，在当前的镇痛疗法中实现阳性临床结果似乎与疼痛的慢性相关。在慢性疼痛患者中的神经影像学研究已经确定了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伤可能是从急性到慢性疼痛的过渡。我们最近在动物疼痛模型中证明，缓解持续的疼痛是有益的，需要伏伏核（NAC）中的多巴胺信号传导。此外，这些缓解疼痛的行为和神经化学测量取决于内源性阿片类神经递质在扣带回皮层（ACC）中，这是编码疼痛厌恶性的区域。慢性疼痛可能会在ACC中产生持续的阿片类药物信号传导，从而导致该区域中阿片类发射器受体功能的进行性变化，并且随着时间的流逝，镇痛效率降低。确定疼痛，脑神经疾病疾病和疼痛疗法对人类的镇痛有效性之间是否存在因果关系是困难的，并且可能是不道德的。因此，我们将采用慢性神经性疼痛的大鼠模型在六个月内进行纵向研究，以更加模仿人类的慢性疼痛状况。在AIM 1中，我们将研究大脑区域中阿片类药物和多巴胺神经传递的暂时变化，以编码疼痛的情感和动机方面。我们将使用快速扫描循环伏安法（FSCV）和快速扫描控制的吸附伏安法（FSCAV）技术，在我们的实验室中率先进行的，可以用前所未有的临时和空间分辨率来测量具有清醒表现的动物的体质和滋补性多巴胺的测量。多巴胺的阶段性释放可能会受到慢性疼痛相关多巴胺水平的变化的影响。此外，我们将使用一种新型的体内微透析方法，涉及在线保存以及LC-MS3检测，以测量在对照和疼痛条件下表现动物的ACC中低水平的内源性阿片类药物。 AIM 2将研究疼痛慢性是否与阿片类药物和多巴胺信号效率降低有关。我们的实验室表明，在动物中，缓解疼痛厌恶性会产生负强化，可以使用条件的位置偏好（CPP）在行为上评估。 CPP可以看作是动物的镇痛效率的“自我报告”，涵盖了学习的疼痛以及持续疼痛的动机和情感特征，因此提供了与人类痛苦经历的转化相关性的信息。我们将使用CPP范式评估正在进行的神经性疼痛的进展，并随着时间的推移评估阿片类药物和非阿片类镇痛药的有效性。 AIM 3将确定使用当前在临床试验中的方法逆转慢性疼痛，是否可以实现多巴胺和阿片类药物功能的归一化。拟议的研究解决了我们所知的差距，包括疼痛相关的脑多巴胺和阿片类药物功能的许可，慢性和可逆性。此外，这些研究可能可以客观地量化慢性，并作为有效缓解疼痛治疗的生物标志物，可以加快转化和发现新的疼痛治疗剂。