Immune and Gilia Regulation of Pain & Analgesic Actions

免疫和吉利亚疼痛调节

• 批准号: 8284453
• 负责人: LINDA WATKINS
• 金额: $ 12.33万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284453
• 关键词: Aging; American; Analgesics; Astrocytes; Blood - brain barrier anatomy; Brain; Cells; Commit; Communities; Development; Education; Event; Fibromyalgia; Funding; Future; Goals; Grant; Hippocampus (Brain); Hospitals; Human; IL10 gene; Immune; Investigation; Mediation; Memory; Mentorship; Messenger RNA; Microglia; Migraine; Modeling; National Institute of Dental and Craniofacial Research; National Institute of Drug Abuse; National Institute of Mental Health; Neuraxis; Neuroglia; Neurons; Opioid; Opioid Analgesics; Pain; Pain Research; Pain management; Peripheral; Phase; Proteins; Rattus; Regulation; Rehabilitation therapy; Research; Research Personnel; Research Project Grants; Role; Senior Scientist Award; Serotonin; Signal Transduction; Spinal; Spinal Cord; Spinal cord injury; Spinal cord injury patients; System; Therapeutic; Translations; Trigeminal System; United States National Institutes of Health; Viral; Work; chronic pain; clinically relevant; cytokine; drug of abuse; gene therapy; immune activation; inhibitor/antagonist; mimicry; non-opioid analgesic; painful neuropathy; programs; relating to nervous system; stressor

The Pi'spreclinical research program seeks to understand how activation of peripheral immune cells and central nervous system glia (microglia and astrocytes) triggers a cascade of events leading to neuronal activation, pathological pain states, and dysregulation of the clinically relevant effects of analgesic drugs. The current research focus is directly relevant to her long-term goals of understanding (a) immune-neural bi- directional interactions, and (b) pain modulation systems. The proposed project is a request for a K05 award for the PI to focus on programmatic investigations of pathological pain states. The currently funded projects include: (a) Immune/glial mediation of exaggerated pain states; NIDA K02 (Watkins PI; 6/03-5/08; DA015642); (b) Pain control via spinal interleukin-10 gene therapy; NIDA CEBRA Phase II (R01; Milligan PI; Watkins coPI; 09/04- 09/09; DA018156); (c) Pain facilitation via neuron-to-glia signaling; NIDA R01 (Watkins PI; 3/05-12/09; DA017670); (d) Opioid analgesics: modulation.of trigeminal & spinal glial activation; NIDCR R01 (Watkins PI; 7/06-4/11; DE017782); (e) Exploration of AV411, a blood brain barrier permeable glial activation inhibitor; Avigen (Watkins Pl;1/06-12/08); (f) Development of rat models to assess potential glial involvement in migraine; GlaxoSmithKline (Watkins PI; 1/07-12/09); (g) Translation from rats to humans: are chronic pain states in humans associated with glial activation in spinal cord and/or brain?; American Fibromyalgia Syndrome Association (Watkins CD Boulder PI; open ended small grant); (h) Human spinal cord glial cytokines & chronic pain NIAMSD R01 (Lorton, PI; Watkins, coPI; 7/07-6/12; AR054647); & (i) mRNA & protein analyses of spinal cord & CSF from spinal cord injury patients with vs without chronic pain; Craig Spinal Cord Injury Treatment & Rehabilitation Hospital (Watkins CU Boulder PI; 9/07-open ended small grant). In addition, projects under review include: (j) Development of opioid therapeutic approaches that fail to activate glia; Covidien (Watkins PI);(k) Exploring the potential of glia for regulating clinically relevant opioid actions, R01 proposal (Watkins PI);and (I) Exploiting viral mimicry to develop new therapies for treating neuropathic pain, R21 proposal (Leinwand PI; Watkins coPI). Thus this is an active & diverse research program exploring multiple levels of analyses at the forefront of pain research. All of these projects are focused on understanding immune/glial regulation of pain and analgesic actions. Beyond this extensive research program, the PI is committed to education of the scientific and lay communities on these topics via review articles and chapters and invited talks, and the mentorship of young investigators.

Pi的临床研究计划旨在了解外周免疫细胞的激活和 中枢神经系统胶质细胞（小胶质细胞和星形胶质细胞）触发一系列事件，导致神经元 激活、病理性疼痛状态和镇痛药物临床相关作用的失调。 目前的研究重点与她的长期目标直接相关，即理解（a）免疫神经双功能， 定向相互作用，和（B）疼痛调节系统。 拟议的项目是为PI申请K 05奖，以专注于以下项目的项目调查： 病理性疼痛状态目前资助的项目包括：（a）免疫/神经胶质介导的夸大的 疼痛状态; NIDA K 02（Watkins PI; 6/03-5/08; DA 015642）;（B）通过脊髓白细胞介素-10基因的疼痛控制 治疗; NIDA CEBRA II期（R 01; Milligan PI; Watkins coPI; 09/04- 09/09; DA 018156）;（c）疼痛 通过神经元-神经胶质信号传导的促进作用; NIDA R 01（Watkins PI; 3/05-12/09; DA 017670）;（d）阿片类 镇痛药：三叉神经和脊髓神经胶质活化的调节; NIDCR R 01（Watkins PI; 7/06-4/11; （e）AV 411（一种血脑屏障可渗透的神经胶质活化抑制剂）的探索; Avigen （Watkins Pl;1/06-12/08）;（f）开发大鼠模型以评估偏头痛中潜在的神经胶质参与; GlaxoSmithKline（Watkins PI; 1/07-12/09）;（g）从大鼠到人类的转化： 人类与脊髓和/或大脑中的神经胶质激活有关？美国纤维肌痛综合征 协会（Watkins CD Boulder PI;开放式小额赠款）; 慢性疼痛NIAMSD R 01（Lorton，PI; Watkins，coPI; 7/07-6/12; AR 054647）;（i）mRNA和蛋白质分析 患有慢性疼痛与不患有慢性疼痛的脊髓损伤患者的脊髓和CSF;克雷格脊髓损伤 治疗和康复医院（Watkins CU Boulder PI; 9/07-无限期小额赠款）。此外，本发明还提供了一种方法， 正在审查的项目包括：（j）开发不能激活神经胶质的类阿片治疗方法; Covidien（Watkins PI）;（k）探索神经胶质细胞调节临床相关阿片类药物作用的潜力，R 01 建议（Watkins PI）;和（I）利用病毒模拟来开发用于治疗神经性疼痛的新疗法， R21提案（Leinwand PI; Watkins coPI）。因此，这是一个积极和多样化的研究计划，探索 在疼痛研究的最前沿进行多层次的分析。所有这些项目都集中在 理解疼痛和镇痛作用的免疫/神经胶质调节。除了这些广泛的研究之外 计划，PI致力于通过审查这些主题的科学和非专业社区的教育 文章和章节和邀请会谈，并指导年轻的调查人员。

项目成果

Adenosine 2A receptor agonism: A single intrathecal administration attenuates motor paralysis in experimental autoimmune encephalopathy in rats.

• DOI: 10.1016/j.bbi.2015.01.014
• 发表时间: 2015-05
• 期刊: BRAIN BEHAVIOR AND IMMUNITY
• 影响因子: 15.1
• 作者: Loram, Lisa C.;Strand, Keith A.;Taylor, Frederick R.;Sloane, Evan;Van Dam, Anne-Marie;Rieger, Jayson;Maier, Steven F.;Watkins, Linda R.
• 通讯作者: Watkins, Linda R.

Toll-like receptors in chronic pain.

• DOI: 10.1016/j.expneurol.2011.09.038
• 发表时间: 2012-04
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Nicotra, Lauren;Loram, Lisa C.;Watkins, Linda R.;Hutchinson, Mark R.
• 通讯作者: Hutchinson, Mark R.

Effect of chronic delivery of the Toll-like receptor 4 antagonist (+)-naltrexone on incubation of heroin craving.

• DOI: 10.1016/j.biopsych.2012.12.019
• 发表时间: 2013-04-15
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Theberge, Florence R.;Li, Xuan;Kambhampati, Santa;Pickens, Charles L.;Laurent, Robyn St.;Bossert, Jennifer M.;Baumann, Michael H.;Hutchinson, Mark R.;Rice, Kenner C.;Watkins, Linda R.;Shaham, Yavin
• 通讯作者: Shaham, Yavin

Intrathecal injection of adenosine 2A receptor agonists reversed neuropathic allodynia through protein kinase (PK)A/PKC signaling.

• DOI: 10.1016/j.bbi.2013.06.004
• 发表时间: 2013-10
• 期刊: BRAIN BEHAVIOR AND IMMUNITY
• 影响因子: 15.1
• 作者: Loram, Lisa C.;Taylor, Frederick R.;Strand, Keith A.;Harrison, Jacqueline A.;RzasaLynn, Rachael;Sholar, Paige;Rieger, Jayson;Maier, Steven F.;Watkins, Linda R.
• 通讯作者: Watkins, Linda R.

Repositioning antimicrobial agent pentamidine as a disruptor of the lateral interactions of transmembrane domain 5 of EBV latent membrane protein 1.

• DOI: 10.1371/journal.pone.0047703
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wang X;Fiorini Z;Smith C;Zhang Y;Li J;Watkins LR;Yin H
• 通讯作者: Yin H