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Stress-induced descending facilitation from amygdala kappa opioid receptors in functional pain

功能性疼痛中杏仁核卡帕阿片受体的压力诱导的下行促进

基本信息

批准号：
9896878
负责人：
Volker Neugebauer
金额：
$ 54.16万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896878
关键词：
Acute Address Affect Affective Agonist Amygdaloid structure Animals Area Behavioral Behavioral Assay Brain Cell Nucleus Chronic Chronic Fatigue Syndrome Clinical Clinical Trials Data Development Disinhibition Dynorphins Electrophysiology (science)Emotional Exposure to Fibromyalgia Frequencies Future Genetic Goals Gulf War Headache Health Human Hyperalgesia Immunohistochemistry Injury Interruption Interstitial Cystitis Investigation Irritable Bowel Syndrome Knowledge Lead Link Mediating Memory Methods Migraine Modeling Molecular Molecular Target Morphine Mus Neuronal Plasticity Neurons Nociception Opioid Opioid Antagonist Output Pain Pain Disorder Pain Research Pain intensity Pain quality Pain-Free Patients Peripheral Pharmaceutical Preparations Physiology Predisposing Factor Receptor Signaling Resolution Rodent Model Sensory Signal Transduction Slice Stimulus Stress Structure Synapses Syndrome System Tactile Hyperalgesias Temporomandibular Joint Disorders Testing Therapeutic Therapeutic Intervention Thermal Hyperalgesias Time United States National Institutes of Health Vulvodynia Work allodynia base behavioral response biological adaptation to stress cell type central sensitization chronic pain clinically relevant dorsal horn dynorphin receptor experience experimental study innovation insight interdisciplinary approach kappa opioid receptors neural circuit neurobiological mechanism norbinaltorphimine novel novel therapeutics optogenetics pain behavior pain patient pain reduction pre-clinical prevent resilience response stressor targeted treatment tissue injury

项目摘要

Project Summary Many patients suffer from chronic pain in the absence of identifiable injury. Such pains are termed “functional” and include irritable bowel syndrome, temporomandibular joint disorder, fibromyalgia, migraine and others. Functional pain patients experience pain free periods that are interrupted by attacks of pain that can persist for variable periods of time. The chronification of these pain disorders has been linked to the number and frequency of attacks suggesting that repeated nociceptive episodes promote and maintain a state of central sensitization that reflects increased vulnerability to future attacks. Functional pain patients commonly identify stress as a key trigger of pain episodes but neurobiological mechanisms remain to be determined. In this project, we test the novel hypothesis that in sensitized states, stress-induced kappa opioid receptor (KOR) signaling in the amygdala promotes functional pain responses. We have developed an injury-free rodent model of stress-related functional pain based on hyperalgesic priming with opioids. Opioids have been shown to produce opioid-induced hyperalgesia (OIH) in humans and in animals. OIH is characterized by generalized tactile and thermal hyperalgesia, decreased nociceptive thresholds, increase temporal summation, and a loss of descending noxious inhibitory controls (DNIC). Following resolution of OIH, and in the absence of stress, animals have normal pain responses. Hyperalgesic priming, however, produces a state of latent sensitization so that animals previously exposed to morphine are now prone to stress-induced hyperalgesia and a loss of DNIC that is prevented by blockade of KOR signaling within the central nucleus of the amygdala (CeA). Our electrophysiological data support a KOR-mediated disinhibition of CeA neurons that promote pain. We will use advanced behavioral and electrophysiological approaches with optogenetic and chemogenetic methods to demonstrate that activation of CeA KOR neurons in control, unprimed mice promotes pain-related responses (Specific Aim 1). These studies will establish the neural circuitry within the amygdala that may underlie a novel KOR-mediated pronociceptive CeA output that is engaged through disinhibition. Specific Aim 2 will determine if exogenous activation of the CeA KOR circuit results in amplified pain responses following priming- induced latent sensitization. In Specific Aim 3 we will determine whether blockade of stress-induced endogenous CeA KOR signaling reduces pain responses following priming-induced latent sensitization. The proposed studies will characterize a previously unknown stress-related KOR mediated hyperalgesic circuit from CeA and determine how this circuit may promote decreased resilience to stress. Importantly, these studies may unravel mechanisms for therapeutic interventions in stress-related functional pain disorders through an actionable molecular target. KOR antagonists are currently in development.

项目总结