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.

慢性疼痛状况困扰着美国20％以上的成年人，强调需要 对疼痛控制机制的更全面了解和更好的疼痛疗法的鉴定。 当前的阿片类药物危机在2020年造成了60,000多名美国人的危机。 阿片类药物非常有效地治疗急性和慢性疼痛，不良副作用，包括滥用 反复使用的责任和对镇痛作用的容忍度，突出了对非阿片类疼痛的需求 疗法。这需要激发我们对乙酰胆碱（ACH）及其受体调节疼痛调节的研究。 从周围到中枢神经系统上升的伤害感受信号传导是由 下降疼痛调节途径，包括腹外侧灰灰色（VLPAG）及其 对腹侧延髓髓质（RVM）的预测。该途径是阿片类药物的关键作用部位 内源性疼痛控制。虽然对此电路知之甚少，但ACH等神经调节剂的影响 该电路，尤其是在慢性疼痛条件下，尚未研究。使用荧光ACH 传感器，我们将研究疼痛和其他行为相关的刺激如何改变ACH释放动态 VLPAG。使用脑切片电生理学，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 药理方法。 我们的初步数据表明，Pedunculopontine Temgentum（PPTG）的胆碱能预测， 调节VLPAG神经元的兴奋性。在慢性疼痛条件下，我们注意到ACH释放的减少 VLPAG和PPTG中的神经元活性降低。我们还发现M2毒蕈碱ACHR在 VLPAG神经元，疼痛增加了这些神经元的活性。这些观察结果使我们 假设慢性疼痛降低了PPTG的胆碱能信号传导，并降低了VLPAG中的M2活性， 导致慢性疼痛症状。我们进一步假设逆转这些变化将减轻 慢性疼痛的体细胞和情感症状。 我们将使用带有体内纤维光度法的ACH传感器来评估急性和慢性疼痛的影响 ACH在VLPAG中释放。我们将使用体内微透析进行ACH来补充这些测定法。大脑切片 电生理学将用于探索突触驱动的疼痛引起的变化和内在的兴奋性的变化 PPTG向VLPAG投射的PPTG胆碱能神经元。体内成像将用于评估引起的慢性疼痛 VLPAG神经元活性的变化。然后，使用化学遗传学和M2 MACHR激动剂，我们将尝试 扭转VLPAG兴奋性的疼痛引起的变化。行为测试将确认逆转 慢性疼痛的体细胞和情感成分。更好地了解这些调节输入 下降的疼痛途径将有助于确定治疗慢性疼痛的新目标。