Midbrain cholinergic modulation of pain states

疼痛状态的中脑胆碱能调节

• 批准号: 10720648
• 负责人: Daniel S McGehee
• 金额: $ 40.65万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720648
• 关键词: Acetylcholine; Acute Pain; Adult; Affective; Affective Symptoms; Agonist; American; Analgesics; Anatomy; Behavior; Behavioral; Biological Assay; Brain; Calcium; Cell Nucleus; Cells; Central Nervous System; Chronic inflammatory pain; Complement; Data; Development; Disinhibition; Electrophysiology (science); Face; Fiber; Genetic; Hyperalgesia; Image; Individual; Interneurons; Investigation; Methods; Microdialysis; Midbrain structure; Molecular; Monitor; Muscarinics; Neuromodulator; Neurons; Nociception; Opioid; Opioid Receptor; Pain; Pain Measurement; Pain management; Pathway interactions; Pattern; Pedunculopontine Tegmental Nucleus; Photometry; Physiological; Physiology; Plague; Public Health; Signal Transduction; Site; Slice; Stimulus; Synapses; System; Testing; United States; abuse liability; allodynia; behavior test; cholinergic; cholinergic neuron; chronic neuropathic pain; chronic pain; chronic pain management; chronic painful condition; effective therapy; endogenous opioids; experimental study; gamma-Aminobutyric Acid; in vivo; in vivo imaging; midbrain central gray substance; neuronal excitability; neurotransmitter release; non-opioid analgesic; novel; novel therapeutics; opioid epidemic; pain inhibition; pain reduction; pain relief; pain sensitivity; pain symptom; pedunculopontine tegmentum; pharmacologic; postsynaptic; presynaptic; receptor; sensor; side effect; two-photon

Chronic pain conditions plague more than 20% of adults in the United States, emphasizing the need for a more comprehensive understanding of pain control mechanisms and identification of better pain therapies. This need is amplified further by the current opioid crisis, which killed over 60,000 Americans in 2020. While opioids are remarkably effective treatments for acute and chronic pain, adverse side effects, including abuse liability and tolerance to the analgesic effects with repeated use, highlight the need for non-opioid pain therapies. This need motivates our investigations of pain modulation by acetylcholine (ACh) and its receptors. Ascending nociceptive signaling from periphery to central nervous system is modulated by the descending pain modulatory pathway, including the ventrolateral periaqueductal grey (vlPAG) and its projections to rostral ventromedial medulla (RVM). This pathway is a crucial site of action of opioids and endogenous pain control. While much is known about this circuitry, the impact of neuromodulators like ACh on this circuit, particularly under chronic pain conditions have not been investigated. Using a fluorescent ACh sensor, we will investigate how pain and other behaviorally relevant stimuli alter ACh release dynamics in the vlPAG. Using brain slice electrophysiology, we will identify the cellular mechanisms behind alterations in ACh release. And finally, we will attempt to reverse these maladaptive ACh dynamics using chemogenetics and pharmacological approaches. Our preliminary data show that cholinergic projections from the pedunculopontine tegmentum (PPTg), modulate excitability of vlPAG neurons. Under chronic pain conditions, we noted a decrease in ACh release in vlPAG and reduced neuronal activity in PPTg. We also found that M2 muscarinic AChRs are expressed on vlPAG neurons, and that pain increases the activity of these neurons. These observations lead us to hypothesize that chronic pain lowers cholinergic signaling from PPTg and reduces M2 activity in vlPAG, contributing to chronic pain symptoms. We further hypothesize that reversing these changes will relieve somatic and affective symptoms of chronic pain. We will use an ACh sensor with in vivo fiber photometry to assess the impact of acute and chronic pain on ACh release in the vlPAG. We will complement these assays using in vivo microdialysis for ACh. Brain slice electrophysiology will be used to explore the pain-induced changes in synaptic drive and intrinsic excitability of PPTg cholinergic neurons that project to vlPAG. In vivo imaging will be used to assess chronic pain induced changes in vlPAG neuronal activity. Then, using chemogenetics and M2 mAChR agonists we will attempt to reverse the pain-induced changes in excitability of vlPAG. Behavioral testing will confirm reversal of the somatic and affective components of chronic pain. Better understanding of these modulatory inputs to descending pain pathways will help identify novel targets for treating chronic pain.

慢性疼痛困扰着超过 20% 的美国成年人，强调需要 更全面地了解疼痛控制机制并确定更好的疼痛疗法。 当前的阿片类药物危机进一步放大了这种需求，这场危机在 2020 年导致 6 万多名美国人死亡。 阿片类药物对于治疗急性和慢性疼痛、不良副作用（包括滥用）非常有效 对重复使用镇痛作用的责任和耐受性，凸显了对非阿片类药物止痛的需求 疗法。这种需求激发了我们对乙酰胆碱 (ACh) 及其受体的疼痛调节的研究。 从外周到中枢神经系统的上行伤害感受信号由 下行疼痛调节通路，包括腹外侧导水管周围灰质 (vlPAG) 及其 延髓头侧腹内侧 (RVM) 的投影。该途径是阿片类药物和阿片类药物作用的关键位点 内源性疼痛控制。虽然人们对这种电路了解很多，但乙酰胆碱等神经调节剂对 该电路，特别是在慢性疼痛条件下尚未得到研究。使用荧光乙酰胆碱 传感器，我们将研究疼痛和其他行为相关刺激如何改变乙酰胆碱释放动态 vlPAG。利用脑切片电生理学，我们将确定 ACh 改变背后的细胞机制 发布。最后，我们将尝试使用化学遗传学和 药理学方法。 我们的初步数据显示，桥脚被盖 (PPTg) 的胆碱能投射， 调节 vlPAG 神经元的兴奋性。在慢性疼痛情况下，我们注意到乙酰胆碱释放减少 vlPAG 和 PPTg 中神经元活性降低。我们还发现 M2 毒蕈碱 AChR 表达于 vlPAG 神经元，而疼痛会增加这些神经元的活动。这些观察使我们得出 假设慢性疼痛会降低 PPTg 的胆碱能信号传导并降低 vlPAG 中的 M2 活性， 导致慢性疼痛症状。我们进一步假设扭转这些变化将缓解 慢性疼痛的躯体和情感症状。 我们将使用具有体内光纤光度测定功能的乙酰胆碱传感器来评估急性和慢性疼痛的影响 vlPAG 中的 ACh 释放。我们将使用体内乙酰胆碱微透析来补充这些测定。脑切片 电生理学将用于探索疼痛引起的突触驱动和内在兴奋性的变化 投射到 vlPAG 的 PPTg 胆碱能神经元。体内成像将用于评估引起的慢性疼痛 vlPAG 神经元活动的变化。然后，使用化学遗传学和 M2 mAChR 激动剂，我们将尝试 逆转疼痛引起的 vlPAG 兴奋性变化。行为测试将确认逆转 慢性疼痛的躯体和情感成分。更好地理解这些调节输入 下行疼痛通路将有助于确定治疗慢性疼痛的新靶标。