8/8 NADIA U01 Long-Term Effects of Adolescent Alcohol on Pain

8/8 NADIA U01 青少年酒精对疼痛的长期影响

基本信息

批准号：
10227251
负责人：
NICHOLAS WARREN GILPIN
金额：
$ 36.75万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10227251
关键词：
Acute Address Adolescence Adolescent Adult Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholic Intoxication Alcohols Amygdaloid structure Analgesics Animals Behavior Behavioral Brain CRISPR/Cas technology Carrageenan Cells Child Child Abuse Chronic Collaborations Corticotropin-Releasing Hormone Data Development Dose Electrophysiology (science)Epigenetic Process Equilibrium Ethanol Exhibits Female Frequencies Goals Human Hyperalgesia Individual Lead Life Literature Long-Term Effects Measures Mechanics Medial Mediating Midbrain structure Modeling Molecular Genetics Neurobiology Neurons Nicotine Withdrawal Nociception Nociceptors Organism Outcome Output Pain Peptides Pharmacology Phenotype Process Rattus Receptor Cell Receptor Gene Receptor Signaling Recording of previous events Reporting Research Risk Risk-Taking Role Severities Sex Differences Sleep disturbances Slice Synapses Synaptic Transmission System Testing Thermal Hyperalgesias Validation Virus Wistar Rats Woman Work adolescent alcohol effect adolescent alcohol exposure alcohol effect alcohol exposure alcohol testing alcohol use disorder anxiety-like behavior base behavioral pharmacology cell type chronic alcohol ingestion chronic pain experimental study inflammatory pain male men midbrain central gray substance neuroadaptation neurobiological mechanism nociceptive response optogenetics pain outcome pain reduction pediatric trauma receptor relating to nervous system response traumatic stress underage drinking vapor

项目摘要

Adolescent alcohol use leads to persistent neural adaptations and behavioral dysregulation that increase the risk of developing alcohol use disorder (AUD). Acute alcohol reduces pain, and chronic pain (e.g., hyperalgesia) can promote alcohol drinking through negative reinforcing analgesic effects. Paradoxically, chronic alcohol produces hyperalgesia or worsen pre-existing pain states. Recently, we reported that medial central amygdala (CeA) projections to a midbrain region called the periaqueductal gray (vlPAG) are critical for mediating hyperalgesia in chronically alcohol exposed adult male rats. This chronic alcohol weakens synaptic connectivity between medial CeA and vlPAG in adult male rats, photostimulation of the CeA-vlPAG circuit rescues hyperalgesia in alcohol-dependent adult rats, and photoinhibition of this circuit produces hyperalgesia in naïve rats. Our lab and others find that antagonism of corticotropin-releasing factor type-1 receptors (CRFR1) in CeA reduces hyperalgesia associated with alcohol withdrawal, nicotine withdrawal and traumatic stress in adult rats. Our overarching hypotheses are that chronic intermittent alcohol exposure in adolescent rats (AIE) produces persist long-term effects on polymodal (i.e., mechanical and thermal) hyperalgesia that is mediated by weakened CeA-vlPAG connectivity and increased CRFR1 signaling in CeA. The CRFR1 signaling gating of CeA-vlPAG function is important for mediating AIE-induced hyperalgesia. We include preliminary data showing that 1) AIE produces rapid and long-lasting thermal and mechanical hyperalgesia during adolescence and that this effect persists into adulthood (Fig. 1), 2) AIE reduces synaptic drive and excitatory/inhibitory ratio on vlPAG-projecting medial CeA neurons in adulthood (Fig. 3), 3) CRFR1 is expressed on vlPAG projecting cells (Fig. 2), and 4) validation data for a CRFR1:cre rat for CRFR1+ cell type- specific modulation of CeA outputs (Fig. 4). Because we also propose to challenge rats with a short-lasting inflammatory pain challenge in adulthood, we have also piloted dose-response effects of carrageenan on nociception in adult Wistar rats. Here, we propose aims that will test the hypotheses that AIE produces hyperalgesia during adolescence that persists into adulthood (Specific Aim 1), that AIE reduces synaptic drive and excitatory/inhibitory balance of synaptic transmission onto vlPAG-projecting CeA neurons via a CRFR1- dependent (Specific Aim 2), and that pharmacological, circuit-based, and epigenetic modulation of CRFR1+ PAG- projecting CeA neurons will rescue AIE-induced hyperalgesia and CeA-vlPAG circuit plasticity (Specific Aim 3). Importantly, we propose specific collaborations with Research Component 6 (PI:Chandler) and 5 (PI: Crews) along with the Epigenetics Core (PI: Pandey) of the NADIA consortium. This proposal focuses on testing adolescent alcohol effects on pain-related outcomes and aligns with the overall goal of the NADIA consortium to examine the effects of adolescent alcohol exposure on the adult organism.

青少年饮酒导致持续的神经适应和行为失调，从而增加患饮酒障碍（AUD）的风险。急性酒精减轻疼痛和慢性疼痛（例如，痛觉过敏）可以通过负增强镇痛作用来促进饮酒。矛盾的是，慢性酒精产生痛觉过敏或较差的先前疼痛状态。最近，我们报道了媒体中央杏仁核（CEA）向中脑区域的项目，称为灰灰色（VLPAG）对于中介至关重要慢性暴露成年雄性大鼠的痛觉过敏。这种慢性酒精削弱了突触连通性在成年雄性大鼠的培养基CEA和VLPAG之间，CEA-VLPAG电路的光刺激酒精依赖性成年大鼠的痛觉过敏，该电路的光抑制会产生痛苦的过敏。老鼠。我们的实验室和其他实验室发现CEA中促肾上腺素释放因子1型受体（CRFR1）的拮抗作用减少成年大鼠戒酒，尼古丁戒断和创伤性压力相关的痛觉过敏。我们的总体假设是，青少年大鼠（AIE）的慢性间歇性酒精暴露会产生持续对弱介导的多峰（即机械和热的）痛觉过敏的长期影响 CEA-VLPAG连接性和CEA中CRFR1信号的增加。 CEA-VLPAG的CRFR1信号门控功能对于介导AIE诱导的痛觉过敏很重要。我们包括初步数据，显示1）AIE产生快速，持久的热和机械青少年期间的痛觉过敏，这种效应一直持续到成年（图1），2）AIE降低了突触驱动器和兴奋性/抑制率在成年期对VLPAG投射介质CEA神经元（图3），3）CRFR1为在VLPAG投影细胞上表达（图2）和4）CRFR1的验证数据：CRFR1+细胞类型的CRE大鼠 CEA输出的特定调制（图4）。因为我们还建议用短暂的挑战老鼠成年后的炎症性疼痛挑战，我们还试图剂量反应的效果成年Wistar大鼠的伤害感。在这里，我们提出的目标将测试AIE产生的假设在青少年期间持续到成年期（特定目标1），AIE降低了合成驱动器（特定目标1）通过CRFR1-- 依赖（特定目标2），以及CRFR1+的药物，基于电路和表观遗传调制 PAG-投影CEA神经元将营救AIE诱导的痛觉过敏和CEA-VLPAG电路可塑性（特定目标3）。重要的是，我们建议与研究组件6（PI：Chandler）和5（PI：：船员）以及纳迪亚财团的表观遗传学核心（PI：Pandey）。该建议重点是测试青少年酒精对与疼痛相关的结果的影响，并与Nadia联盟的总体目标保持一致检查青少年酒精暴露对成人生物体的影响。