Prenatal alcohol exposure generates vulnerability to the proinflammatory effects of morphine and adverse neuroimmune consequences

产前酒精暴露容易受到吗啡的促炎作用和不良神经免疫后果的影响

• 批准号: 10577768
• 负责人: Shahani Noor
• 金额: $ 37.96万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577768
• 关键词: Acute; Adult; Alcohol abuse; Alcohols; Animal Model; Astrocytes; Behavioral; Biological; Cells; Central Nervous System; Chronic; Clinical; Clinical Research; Cognitive; Curiosities; Data; Disease susceptibility; Dose; Down-Regulation; Elderly; Endogenous Factors; Etiology; Evaluation; Family; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; Functional disorder; Future; Gene Expression Profiling; Goals; High Prevalence; Hyperalgesia; Immune; Immune System Diseases; Immunologic Receptors; Individual; Infiltration; Inflammasome; Inflammatory; Injury; Interleukin-1 beta; Investigation; Light; Macrophage; Macrophage Activation; Mediating; Messenger RNA; Minor; Modeling; Morphine; Mus; Naloxone; Nerve; Neuroglia; Neuroimmune; Neurologic Dysfunctions; Opioid; Outcome; Pain; Pain management; Pathologic; Pathology; Pathway interactions; Peripheral; Physiological Adaptation; Population; Predisposition; Pregnancy; Prevalence; Process; Production; Proteins; Public Health; Rattus; Receptor Activation; Receptor Signaling; Recording of previous events; Risk; Risk Factors; Role; Signal Transduction; Spinal; Substance Use Disorder; Substance abuse problem; TNF gene; Therapeutic; Toll-like receptors; Touch sensation; Transcription Initiation; Untranslated RNA; Vertebral column; Work; alcohol exposure; allodynia; antagonist; cell type; chronic pain management; circular RNA; cytokine; enhancing factor; in vivo; marenostrin; mouse model; mu opioid receptors; nerve injury; neurobehavioral; novel; offspring; opioid exposure; opioid misuse; overexpression; pre-clinical; receptor; response; risk mitigation; single-cell RNA sequencing; stem; substance use

PROJECT SUMMARY Exposure to alcohol during gestation can lead to a constellation of mild to severe cognitive and behavioral deficits referred to as Fetal Alcohol Spectrum Disorders (FASD), having a US prevalence as high as ~4.8%. Although clinical studies on long-term consequences of prenatal alcohol exposure (PAE) are sparse, high prevalence of substance use (e.g., alcohol, opioids) is observed in adult FASD populations which may stem from aberrant neuroimmune interactions following exposure to alcohol or opioids. This proposal examines whether PAE induces susceptibility to neuroimmune dysfunction following opioid pain therapy in animal models. In PAE animal models, heightened production of proinflammatory cytokines including interleukin-1β (IL-1β) in the adult central nervous system (CNS) is observed. Our recent work in animal models suggest that PAE is a risk factor for developing CNS pathology such as pathological pain (allodynia) through the actions of spinal astrocyte and macrophage activation by their release of IL-1β and tumor necrosis factor-α (TNF-α). A critical innate immune receptor underlying increased IL-1β and TNF-α is Toll Like Receptor (TLR4), that upon its activation, produces downstream NLRP3 inflammasome signaling and consequent IL-1β. Curiously, morphine, a standard pain therapeutic acting on the μ-opioid receptor, also activates proinflammatory TLR4 signaling resulting in opponent processes; µ-opioid cellular actions to blunt pain and immune TLR4 cellular actions that cause pain. Consequently, higher doses of morphine may be required to achieve pain alleviation in some populations. Based on this background, we speculate that PAE may generate biological vulnerability to CNS pathology by sensitizing TLR4 responses to endogenous factors and morphine that readily interact with TLR4. Thus, one goal of this proposal is to identify if morphine treatment in mice unmasks the insidious effects of PAE on neuroimmune function resulting in chronic CNS pathological consequences. Preliminary data show morphine exposure paradoxically prolongs the course of allodynia in minor nerve-injured adult PAE mice. The potential convergence of PAE and opioid-induced TLR4 actions is entirely unexplored. Therefore, our hypothesis is: PAE primes the TLR4-NLRP3-IL-1β pathway that is unmasked by endogenous pain-enhancing factors and morphine interacting with TLR4 resulting in chronic pathological neuroimmune function. The Aims of the proposal will determine if : (I) PAE augments morphine-mediated TLR4 &/or NLRP3 activation in minor nerve-injured mice causing prolonged allodynia, (II) PAE sensitizes the effects of morphine on TLR4/NLRP3 responses in spinal astrocytes and peripheral macrophages, and (III) the contribution of non-coding circ-Vopp1 dysregulation in PAE-primed TLR4 signaling in response to morphine. Results will provide new evidence for PAE as a risk factor for adverse opioid responses and will identify novel targets to mitigate the risk of neuroimmune dysfunction from adverse TLR4 actions in individuals with FASD.

项目概要 怀孕期间接触酒精会导致一系列轻度到重度的认知和行为问题 这种缺陷被称为胎儿酒精谱系障碍 (FASD)，在美国的患病率高达 4.8%。 尽管关于产前酒精暴露 (PAE) 长期后果的临床研究很少，但 在成人 FASD 人群中观察到药物滥用（例如酒精、阿片类药物）的流行，这可能会导致 暴露于酒精或阿片类药物后异常的神经免疫相互作用。该提案审查了 PAE 是否会导致动物在阿片类药物疼痛治疗后对神经免疫功能障碍的易感性 模型。在 PAE 动物模型中，促炎细胞因子（包括白细胞介素 1β）的产生增加 在成人中枢神经系统（CNS）中观察到（IL-1β）。我们最近在动物模型方面的工作表明 PAE 是发生中枢神经系统病理学的危险因素，例如通过以下行为引起的病理性疼痛（异常性疼痛） 脊髓星形胶质细胞和巨噬细胞通过释放 IL-1β 和肿瘤坏死因子-α (TNF-α) 进行激活。一个 IL-1β 和 TNF-α 增加的关键先天免疫受体是 Toll 样受体 (TLR4)， 它的激活产生下游 NLRP3 炎性体信号传导和随后的 IL-1β。奇怪的是， 吗啡是一种作用于 μ-阿片受体的标准疼痛治疗药物，也可激活促炎性 TLR4 信号导致对手进程； µ-阿片类细胞作用可减轻疼痛并免疫 TLR4 细胞 引起疼痛的行为。因此，可能需要更高剂量的吗啡才能缓解疼痛 一些人群。基于此背景，我们推测 PAE 可能会产生生物脆弱性 通过使 TLR4 对容易与吗啡相互作用的内源因子和吗啡反应敏感来进行中枢神经系统病理学研究 TLR4。因此，该提案的一个目标是确定对小鼠进行吗啡治疗是否会揭示其潜在的影响 PAE 对神经免疫功能的影响导致慢性中枢神经系统病理后果。初步数据显示 矛盾的是，吗啡暴露会延长轻微神经损伤的成年 PAE 小鼠的异常性疼痛过程。这 PAE 和阿片类药物诱导的 TLR4 作用的潜在融合尚未完全被探索。因此，我们的 假设是：PAE 启动 TLR4-NLRP3-IL-1β 通路，该通路被内源性疼痛增强所揭示 因子和吗啡与 TLR4 相互作用，导致慢性病理性神经免疫功能。目标 该提案的内容将确定是否：(I) PAE 在较小程度上增强吗啡介导的 TLR4 和/或 NLRP3 激活 神经损伤小鼠引起长时间异常性疼痛，(II) PAE 使吗啡对 TLR4/NLRP3 的作用敏感 脊髓星形胶质细胞和外周巨噬细胞的反应，以及 (III) 非编码 circ-Vopp1 的贡献 PAE 引发的 TLR4 信号传导因吗啡而失调。结果将为 PAE 是阿片类药物不良反应的一个风险因素，并将确定新的目标来减轻阿片类药物不良反应的风险 FASD 患者 TLR4 不良行为导致神经免疫功能障碍。