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道抑郁症。呼吸道 阿片类药物的抑制作用主要是由G蛋白门控向内整流钾通道介导的 亚基2（GIRK2）由呼吸节律产生的bötzinger络合物的神经元表达。 已知GIRK2在阿片类药物诱导的镇痛中暗示。但是，生化和代谢 与bötzinger和脑干疼痛敏感部位中GIRK2的阿片类药物激活相关的变化 由于腹侧髓质（RVM），仍然未知。在本研究中，我们假设 与长期皮下相关的RVM和Bötzinger络合物的代谢组变化 吗啡给药，是由于由GIRK2通道的激活引起的 RVM和Neurokinin-1受体（NK-1R）表达节奏的节奏细胞的细胞 复杂的; 2）这种激活导致兴奋与抑制之间的失衡 神经递质及其代谢产物在pre-Bötzinger复合物和RVM附近。 我们将使用体内质子磁共振光谱（1H MRS）在野生型和 GIRK2杂合（Girk2 +/-）突变小鼠。我们将分析谷氨酸浓度的变化， 之前，谷氨酰胺，GABA，甘氨酸和其他代谢产物和其他代谢物和RVM和6-7天之前 地下植入吗啡（75 mg颗粒）和/或安慰剂颗粒（对照）之后。结果将 提供有关与吗啡激活相关的细胞和生化变化的有价值的信息 pre-Bötzinger和rvm的Girk2的of。结果也有可能使大脑的研究 参与RVM处OIOID诱导的镇痛作用的代谢产物和OIOID诱导的呼吸道抑郁症在 前Bötzinger综合体。 OMB No. 0925-0001/0002（Rev. 03/2020通过02/28/2023批准）页面延续格式页面