Cholinergic modulation of Descending Pain Control Pathways

下行疼痛控制通路的胆碱能调节

基本信息

  • 批准号:
    10317942
  • 负责人:
  • 金额:
    $ 43.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Daniel S McGehee其他文献

THE EFFECT OF BOTULINUM TOXIN A ON CHEMICAL STIMULATION OF RAT DORSAL ROOT GANGLION CELLS
  • DOI:
    10.1016/s0022-5347(08)60225-6
  • 发表时间:
    2008-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    W Stuart Reynolds;Alvaro Lucioni;David E Rapp;Gregory T Bales;Daniel S McGehee
  • 通讯作者:
    Daniel S McGehee
Opposing Motor Memories in the Direct and Indirect Pathways of the Basal Ganglia
基底神经节直接和间接通路中的相反运动记忆
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kailong Wen;Zhuoyue Shi;Peijia Yu;Lillian Mo;Shivang Sullere;Victor Yang;Nate Westneat;J. Beeler;Daniel S McGehee;Brent Doiron;Xiaoxi Zhuang
  • 通讯作者:
    Xiaoxi Zhuang
Nicotinic Receptors Regulate the Dynamic Range of Dopamine Release in Vivo 3
烟碱受体调节 Vivo 3 中多巴胺释放的动态范围
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
    J. Koranda;J. J. Cone;Daniel S McGehee;Mitchell F. Roitman;J. Beeler;Xiaoxi Zhuang;J. Beeler
  • 通讯作者:
    J. Beeler

Daniel S McGehee的其他文献

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{{ truncateString('Daniel S McGehee', 18)}}的其他基金

Midbrain cholinergic modulation of pain states
疼痛状态的中脑胆碱能调节
  • 批准号:
    10720648
  • 财政年份:
    2023
  • 资助金额:
    $ 43.87万
  • 项目类别:
Mechanisms underlying GLP-1 receptor mediated relief of Parkinson’s disease symptoms
GLP-1 受体介导缓解帕金森病症状的机制
  • 批准号:
    9765998
  • 财政年份:
    2019
  • 资助金额:
    $ 43.87万
  • 项目类别:
Preventing Experience Dependent Aberrant Plasticity Under Dopamine Deficiency
预防多巴胺缺乏下的经验依赖性异常可塑性
  • 批准号:
    9920220
  • 财政年份:
    2016
  • 资助金额:
    $ 43.87万
  • 项目类别:
Preventing Experience Dependent Aberrant Plasticity Under Dopamine Deficiency
预防多巴胺缺乏下的经验依赖性异常可塑性
  • 批准号:
    9188890
  • 财政年份:
    2016
  • 资助金额:
    $ 43.87万
  • 项目类别:
Cellular Basis of Nicotine Induced Aversion
尼古丁引起厌恶的细胞基础
  • 批准号:
    8830958
  • 财政年份:
    2014
  • 资助金额:
    $ 43.87万
  • 项目类别:
Cellular Basis of Nicotine Induced Aversion
尼古丁引起厌恶的细胞基础
  • 批准号:
    8722770
  • 财政年份:
    2014
  • 资助金额:
    $ 43.87万
  • 项目类别:
SYNAPTIC TRANSMISSION AND SENSITIZATION TO NICOTINE
突触传递和对尼古丁的敏感性
  • 批准号:
    7287657
  • 财政年份:
    2007
  • 资助金额:
    $ 43.87万
  • 项目类别:
Nicotinic Modulation of the Mesoaccumbens DA System
Mesoaccembens DA 系统的烟碱调节
  • 批准号:
    6581526
  • 财政年份:
    2003
  • 资助金额:
    $ 43.87万
  • 项目类别:
Nicotinic Modulation of the Mesoaccumbens DA System
Mesoaccembens DA 系统的烟碱调节
  • 批准号:
    6846558
  • 财政年份:
    2003
  • 资助金额:
    $ 43.87万
  • 项目类别:
Nicotinic Modulation of the Mesoaccumbens Dopamine System
中伏多巴胺系统的烟碱调节
  • 批准号:
    7172327
  • 财政年份:
    2003
  • 资助金额:
    $ 43.87万
  • 项目类别:

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适应性行为和反应模式中乙酰胆碱活性的时空动态
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