Howard University Research Center for Minority Health and Health Disparities

霍华德大学少数族裔健康与健康差异研究中心

• 批准号: 10559951
• 负责人: William M. Southerland
• 金额: $ 7.73万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10559951
• 关键词: Absence of pain sensation; Acute; Age; Analgesics; Biochemical; Brain; Brain Stem; Brain region; Cause of Death; Cells; Chemicals; Chronic; Complex; DNA Sequence Alteration; Development; Doctor of Philosophy; GIRK2 subunit, G protein-coupled inwardly-rectifying potassium channel; GTP-Binding Proteins; Glutamates; Glutamine; Glycine; Implant; Inositol; Knowledge; Life; Magnetic Resonance Spectroscopy; Measures; Mediating; Metabolic; Microinjections; Morphine; Mus; Mutant Strains Mice; N-acetylaspartate; NMR Spectroscopy; Naltrexone; Neurons; Neurotransmitters; Opioid; Opioid Analgesics; Opioid Antagonist; Opioid agonist; Pain; Pain management; Placebo Control; Placebos; Play; Principal Investigator; Property; Protons; Rattus; Research; Respiration; Respiratory Center; Role; Site; Substance P Receptor; Testing; Universities; Ventilatory Depression; Wild Type Mouse; gamma-Aminobutyric Acid; health disparity; implantation; in vivo; in vivo magnetic resonance spectroscopy; inward rectifier potassium channel; metabolomics; minority health disparity; morphine administration; mu opioid receptors; neurochemistry; novel; opioid abuse; opioid exposure; opioid overdose; opioid use; programs; respiratory; side effect; subcutaneous; treatment strategy

Program Director/Principal Investigator (Last, First, Middle): Ozra Dehkordi, Ph.D ABSTRACT The most frequent cause of death associated with opioid overdose is respiratory depression. The respiratory depressant effects of opioids are mainly mediated by G-protein-gated inward rectifying potassium channels subunit 2 (GIRK2) expressed by the respiratory rhythm generating neurons of the pre-Bötzinger complex. GIRK2 are also known to be implicated in opioid-induced analgesia. However, biochemical and metabolic changes associated with opioid activation of GIRK2 in the pre-Bötzinger and brainstem pain sensitive sites such as rostral ventral medulla (RVM), is still unknown. In the present study in mice, we hypothesize that 1) the metabolomic changes in the RVM and pre-Bötzinger complex associated with long-term subcutaneous morphine administration, is due to activation of GIRK2 channels expressed by pain sensitive cells of the RVM and neurokinin-1 receptor (NK-1R) expressing rhythm generating cells of the pre-Bötzinger complex; and that 2) this activation leads to an imbalance between excitatory and inhibitory neurotransmitters and their metabolites in the immediate vicinity of pre-Bötzinger complex and RVM. We will test this hypothesis using in vivo proton magnetic resonance spectroscopy (1H MRS) in wild-type and GIRK2 heterozygous (GIRK2+/-) mutant mice. We will analyze changes in the concentration of glutamate, glutamine, GABA, glycine and other metabolites in the pre-Bötzinger complex and RVM before and 6-7 days after subcutaneous implantation of morphine (75 mg pellets) and/ or placebo pellets (control). The results will provide valuable information regarding cellular and biochemical changes associated with morphine activation of GIRK2 at the pre-Bötzinger and RVM. The results also has the potential to enable the study of brain metabolites involved in opioid-induced analgesia at the RVM and opioid-induced respiratory depression at the pre- Bötzinger complex. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

项目总监/首席研究员（最后、第一、中间）：Ozra Dehkordi，博士 抽象的 与阿片类药物过量相关的最常见死亡原因是呼吸抑制。 阿片类药物的抑制作用主要由 G 蛋白门控内向整流钾通道介导 亚基 2 (GIRK2) 由前 Bötzinger 复合体的呼吸节律生成神经元表达。 GIRK2 也被认为与阿片类药物引起的镇痛有关，然而，生化和代谢方面。 与阿片类药物激活前 Bötzinger 和脑干疼痛敏感位点 GIRK2 相关的变化，例如 作为延髓头端腹侧（RVM），目前尚不清楚，在目前的小鼠研究中，我们渴望 1）。 RVM 和前 Bötzinger 复合体的代谢组学变化与长期皮下注射相关 吗啡给药是由于疼痛敏感细胞表达的 GIRK2 通道激活所致。 前 Bötzinger 表达节律生成细胞的 RVM 和神经激肽-1 受体 (NK-1R) 复杂；2）这种激活导致兴奋性和抑制性之间的不平衡 前 Bötzinger 复合体和 RVM 附近的神经递质及其代谢物。 我们将使用体内质子磁共振波谱 (1H MRS) 在野生型和 我们将分析 GIRK2 杂合子 (GIRK2+/-) 突变小鼠的谷氨酸浓度变化， 前Bötzinger复合物和RVM中的谷氨酰胺、GABA、甘氨酸和其他代谢物之前和6-7天 皮下植入吗啡（75 毫克颗粒）和/或安慰剂颗粒（对照）后，结果将。 提供与吗啡激活相关的细胞和生化变化的有价值的信息 GIRK2 在 pre-Bötzinger 和 RVM 上的研究结果也有可能促进大脑的研究。 参与阿片类药物引起的 RVM 镇痛和阿片类药物引起的呼吸抑制的代谢物 前 Bötzinger 复合体。 OMB 编号 0925-0001/0002（修订版 03/2020 已批准至 02/28/2023） 页面延续格式页面