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Dissecting circuits mediating pain-induced alterations in motivated behavior

剖析介导疼痛引起的动机行为改变的回路

基本信息

批准号：
9246764
负责人：
Jose A Moron-Concepcion
金额：
$ 45.24万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9246764
关键词：
Acute Pain Affect Agonist Animals Behavior Behavioral Brain Clinic Clinical Clinical Treatment Data Development Dopamine Dose Down-Regulation Electrophysiology (science)Freund&apos s Adjuvant Functional disorder Genetic Human Image Impairment Individual Inflammation Intake Laboratories Lead Learning Leucine Enkephalin Link Mediating Microdialysis Morphine Motivation Mus Neurons Nociception Nucleus Accumbens Opiate Addiction Opiates Opioid Opioid Peptide Optics Output Overdose Pain Pathologic Pathway interactions Periodicity Pharmaceutical Preparations Phenotype Process Property Psychological reinforcement Receptor Signaling Reporting Rewards Role Scanning Self Administration Sensory Signal Transduction Spinal Cord Stimulus Structure System Testing Ventral Tegmental Area Work chronic pain desensitization drug reward endogenous opioids in vivo in vivo calcium imaging inflammatory pain interdisciplinary approach loss of function mesolimbic system microendoscopy motivated behavior mu opioid receptors multidisciplinary neural circuit neuromechanism novel opioid abuse opioid use optogenetics pre-prodynorphin prevent receptor function reinforcer response reward processing tool transmission process

项目摘要

Maladaptive pain-induced dysfunction in motivational circuits are the likely critical factors that lead to pathological alterations in natural and drug reward seeking behaviors, yet the neural circuit mechanisms for these effects are largely unknown. The mesolimbic system is a key network node that integrates pain and reward. Dopamine (DA) transmission in the mesolimbic system, via the VTA to NAc has long been recognized for its role in motivated behavior. Alterations in DA signaling within the mesolimbic pathway are associated with motivational deficits, and animals in pain show impaired motivated responses to natural and drug reward. Importantly, from a translational perspective, negative correlations between pain and mesolimbic DA activity in humans have been often reported. Mu opioid receptor (MOPR) agonists are positively reinforcing and remain the predominant opioids used for alleviating clinical pain and recreational use/abuse. We recently found that persistent inflammatory pain downregulates function of MOPR in the VTA with a concomitant loss of opioid- induced DA release in the NAc in a dose-dependent manner leading to increase intake of higher doses of opioids which are known to contribute to abuse-associated phenotypes. In addition, our preliminary data suggest that persistent inflammation causes an increase in endogenous opioid tone which is likely leading to desensitization of MOPR in the VTA. Collectively, these findings suggest that pain suppresses VTANAc neural circuit activity through suppression of mesolimbic DA release. We predict that this effect is mediated by an increase in endogenous opioid tone and reduction of MOPR function in the VTA which negatively impact the animal's motivational state contributing to an opioid abuse-associated phenotype. In this application we propose cross disciplinary cutting-edge approaches to dissect the neuronal and cellular mechanisms underlying the downregulation of mu-opioid circuits in the presence of inflammatory pain. In three specific aims we will: i) determine the mechanisms for downregulation of mu-opioid-containing GABAergic circuits in inflammatory pain ii) determine whether increases in endogenous mu-opioid agonist tone changes mu-opioid function, and whether these processes are necessary and sufficient for the effects of inflammatory pain on motivated behavior. Finally, in a third aim we will directly visualize endogenous opioid-containing neuronal ensembles during the development of inflammatory pain and decreased motivational states. Here we will determine whether mu-opioid receptors, their endogenous agonists, within discrete mesolimbic neural circuits, are necessary and sufficient to mediate pain-induced alterations in opioid intake and motivated behavior.

动机回路中的不适应疼痛引起的功能障碍可能是导致