Cholinergic modulation of Descending Pain Control Pathways

下行疼痛控制通路的胆碱能调节

• 批准号: 10317942
• 负责人: Daniel S McGehee
• 金额: $ 43.87万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317942
• 关键词: Absence of pain sensation; Acetylcholine; Acute Pain; Address; Adult; Affective; Agonist; American; Analgesics; Anatomy; Biological Assay; Brain; Cell Nucleus; Cells; Cholinergic Receptors; Chronic; Communication; Country; Data; Electrophysiology (science); Face; Fluorescent in Situ Hybridization; Glutamates; Goals; Histologic; Hyperalgesia; Individual; Inflammatory; Infusion procedures; Investigation; Knowledge; Mechanics; Mediating; Modeling; Morphine; Mus; Muscarinics; Naloxone; Neuraxis; Neurons; Neuropathy; Neuropeptides; Neurotransmitters; Nociception; Opioid; Opioid Receptor; Pain; Pain Measurement; Pain management; Pathway interactions; Pedunculopontine Tegmental Nucleus; Pharmaceutical Preparations; Pharmacology; Plague; Public Health; Reproducibility; Role; Signal Transduction; Site; Slice; Source; Synapses; System; Testing; Time; United States; Withdrawal; allodynia; base; cell type; cholinergic; chronic neuropathic pain; chronic pain; chronic painful condition; drug discovery; effective therapy; efficacy testing; experience; experimental study; gamma-Aminobutyric Acid; in vivo; mRNA Expression; midbrain central gray substance; morphine tolerance; nerve injury; non-opioid analgesic; novel; novel therapeutic intervention; opioid epidemic; opioid overdose; opioid use; optical fiber; optogenetics; overdose death; pain model; pain relief; pain signal; painful neuropathy; preference; prescription opioid; receptor; retrograde transport; side effect; spared nerve; statistics; transmission process

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 better pain therapies. This need is amplified further by the current opioid crisis, which killed 47,600 Americans in 2018. 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 novel non-opioid pain therapies. This need motivates our investigations of pain modulation by acetylcholine (ACh) and its receptors (AChRs) in the ventrolateral periaqueductal gray (vlPAG). Ascending pain signaling from periphery to central nervous system is modulated by the descending pain pathway, including the vlPAG and its projections to rostral ventromedial medulla (RVM) and locus ceruleus (LC). This descending pain pathway is a key site of action of opioids and endogenous pain control. While much is known about this circuitry, the pain modulatory effects of cholinergic inputs to vlPAG are understudied. Our preliminary data show that optogenetic stimulation of cholinergic projections from the pedunculopontine tegmental nucleus (PPTg) to vlPAG is antinociceptive in acute pain. Using cell- and circuit-specific optogenetic approaches, we will test the effect of stimulating cholinergic projections to vlPAG on nociception in a chronic neuropathic pain model, identify the cholinergic receptors mediating these antinociceptive effects, and explore possible interactions between cholinergic signaling and the opioid system. In Aim 1, we will use optogenetic approaches to test antinociceptive effects of stimulating cholinergic PPTg neurons projecting to vlPAG in mice experiencing chronic neuropathic pain. We will also assay affective pain relief of stimulating these projections using a real-time place preference assay. In Aim 2, we will identify cholinergic receptor(s) mediating synaptic communication between PPTg and vlPAG neurons, using high- throughput fluorescence in situ hybridization assay to visualize mRNA expression of muscarinic and nicotinic AChRs on vlPAG neurons. After identifying candidate AChR(s) based on mRNA expression, we will test functional role of these receptors in synaptic communication, using slice electrophysiology and ex vivo optogenetics. Finally, we will test the causal role of identified AChRs in antinociception in vivo using optogenetics and pharmacology in neuropathic pain assays. In Aim 3, we will explore possible interactions between these cholinergic mechanisms and the opioid system, by testing the efficacy of cholinergic analgesia in morphine-tolerant mice and during naloxone precipitated withdrawal from chronic morphine treatment. These studies will employ histological, electrophysiological, optogenetic and pharmacological approaches to advance our knowledge of cholinergic modulation of descending pain pathways, to ultimately help identify novel opioid-independent targets for treating chronic pain.

在美国，慢性疼痛困扰着超过20%的成年人，这就强调了采取更多措施的必要性