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

• 批准号: 10074983
• 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
• 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/10074983
• 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

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.

青少年饮酒会导致持续的神经适应和行为失调，从而增加 发生酒精使用障碍 (AUD) 的风险。急性酒精可减轻疼痛，而慢性疼痛（例如痛觉过敏）。 矛盾的是，长期饮酒可以通过负面增强镇痛作用促进饮酒。 产生痛觉过敏或使已有的疼痛状态恶化 最近，我们报道了内侧中央杏仁核。 (CeA) 投射到称为导水管周围灰质 (vlPAG) 的中脑区域对于调节至关重要 长期暴露于酒精的成年雄性大鼠的痛觉过敏这种长期酒精会削弱突触连接。 成年雄性大鼠的内侧 CeA 和 vlPAG 之间，CeA-vlPAG 回路的光刺激可以挽救 在酒精依赖的成年大鼠中产生痛觉过敏，而该电路的光抑制在幼稚大鼠中产生痛觉过敏 我们的实验室和其他人发现 CeA 中促肾上腺皮质激素释放因子 1 型受体 (CRFR1) 具有拮抗作用。 减少成年大鼠与酒精戒断、尼古丁戒断和创伤应激相关的痛觉过敏。 我们的首要假设是，青少年大鼠慢性间歇性酒精暴露（AIE）会产生 对由弱化介导的多模式（即机械和热）痛觉过敏持续存在长期影响 CeA-vlPAG 连接性和 CeA 中 CRFR1 信号传导的增加 CeA-vlPAG 的 CRFR1 信号传导门控。 功能对于介导 AIE 引起的痛觉过敏很重要。 我们提供的初步数据表明 1) AIE 产生快速且持久的热力和机械力 青春期痛觉过敏，并且这种效应持续到成年期（图 1），2）AIE 突触 成年期 vLPAG 投射的内侧 CeA 神经元的驱动和兴奋/抑制比（图 3），3）CRFR1 是 在 vLPAG 投射细胞上表达（图 2），以及 4）CRFR1:cre 大鼠 CRFR1+ 细胞类型的验证数据 - CeA 输出的特定调节（图 4）因为我们还建议用短期的挑战大鼠。 为了应对成年期的炎症性疼痛挑战，我们还试验了角叉菜胶的剂量反应效应 在这里，我们提出了测试 AIE 产生的假设的目标。 青春期痛觉过敏持续到成年（具体目标 1），AIE 降低突触驱动 通过 CRFR1- 突触传递到 vlPAG 投射的 CeA 神经元的兴奋/抑制平衡 依赖性（具体目标 2），以及 CRFR1+ 的药理学、基于电路和表观遗传的调节 PAG 投射的 CeA 神经元将挽救 AIE 诱导的痛觉过敏和 CeA-vlPAG 回路可塑性（具体 目标 3) 重要的是，我们建议与研究部分 6（PI：Chandler）和 5（PI：Chandler）进行具体合作。 Crews）与 NADIA 联盟的表观遗传学核心（PI：Pandey）一起该提案侧重于测试。 青少年酒精对疼痛相关结果的影响，符合 NADIA 联盟的总体目标 检查青少年酒精暴露对成人机体的影响。