Neural Transplants and Spinal Neuropathic Pain Processes

神经移植和脊髓神经性疼痛过程

• 批准号: 7912471
• 负责人: Jacqueline Sagen
• 金额: $ 10.1万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912471
• 关键词: Acids; Adrenal Glands; Behavioral; Cell Survival; Cells; Chromaffin Cells; Chronic; Clinical; Embryo; Evaluation; FOS gene; Fibroblast Growth Factor 2; Formalin; Functional disorder; Glial Differentiation; Goals; Injury; Interneurons; Interruption; Intervention; Lead; Modeling; Motivation; Neural Inhibition; Neuraxis; Neurons; Neuropathy; Pain; Peripheral; Peripheral Nerves; Peripheral nerve injury; Physiological; Posterior Horn Cells; Process; Production; Sensory Process; Shock; Sorting - Cell Movement; Source; Spinal; Spinal Cord; Spinal cord injury; Stem cell transplant; Stimulus; System; Transplantation; base; cell preparation; central pain; chronic constriction injury; chronic pain; comparative; constriction; dorsal horn; gamma-Aminobutyric Acid; genetic manipulation; improved; nerve stem cell; neurochemistry; neuron loss; neuronal excitability; neuropathology; painful neuropathy; promoter; relating to nervous system; response; restoration; spinal cord injury pain; traditional therapy; transcription factor; transmission process

Pain from injury to the peripheral or central nervous system is often persistent and debilitating, and presents a significant clinical challenge as it does not respond well to traditional therapies. The underlying hypothesis and motivation for the proposed studies is that severe chronic pain from spinal cord or peripheral nerve injury results from loss of spinal inhibitory processes and consequent abnormal hyperexcitability in dorsal horn pain transmission neurons, and that restoration of spinal inhibition by neural transplantation will alleviate neuropathic pain. In order to accomplish this, peripheral and central models of injury-induced pain will be evaluated for neuropathology and stem cell transplantation strategies. The chronic constriction injury model (CCI) will be used for peripheral neuropathic pain and the quisqualic acid model (QUIS) for excitotoxic spinal cord injury pain. Aim 1 will characterize and compare the inhibitory neuronal cell loss in the spinal dorsal horn and consequent exaggerated pain following CCI and QUIS. Aim 2 will characterize and compare the abnormal activation and hyperexcitability of spinal dorsal horn neurons following CCI and QUIS. Studies in these 2 aims will includes in depth evaluation of morphological and neurochemical changes in the spinal dorsal horn that likely contribute to inhibitory loss and abnormal hyperexcitability (GABA neuronal loss or dysfunction), alterations in sensory processing (exaggerated behavioral responses and c-fos activation in response to noxious and innocuous stimuli), and physiological alterations in dorsal horn neuronal excitability to establish a comparative basis between the models and treatment interventions. Aims 3-5 will explore the use of neural progenitor transplants to replace lost or dysfunctional inhibitory neurocircuitry in the spinal dorsal horn following peripheral nerve or spinal cord injury. Aim 3 will generate a reliable and reproducible source of GABAergic neural progenitor cells for transplantation using extrinsic manipulation (trophic factor shock), genetic manipulation (blocking HLH transcription factor Hes1 to promote GABAergic differentiation) and/or cell selection (GADpromoter-GFP and FACS sorting). Aim 4 will evaluate GABAergic neural progenitor transplantation strategies in restoring spinal inhibition and alleviating chronic neuropathic and central pain. Aim 5 will evaluate chromaffin cell and GABAergic neural progenitor co-grafting strategies, as chromaffin cells produce a cocktail of trophic factors which improve neural stem cell survival and differentiation, and can reduce chronic neuropathic and SCI pain. Findings from these studies should lead to improved interventive strategies in the management of intractable neuropathic pain.

外周或中枢神经系统损伤引起的疼痛通常是持久的，使人虚弱，并出现

项目成果

Intraspinal transplantation of GABAergic neural progenitors attenuates neuropathic pain in rats: a pharmacologic and neurophysiological evaluation.

• DOI: 10.1016/j.expneurol.2011.12.005
• 发表时间: 2012-03
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Jergova, Stanislava;Hentall, Ian D.;Gajavelli, Shyam;Varghese, Mathew S.;Sagen, Jacqueline
• 通讯作者: Sagen, Jacqueline

Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy.

• DOI: 10.1016/j.neuropharm.2014.11.024
• 发表时间: 2015-08
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Nasirinezhad F;Jergova S;Pearson JP;Sagen J
• 通讯作者: Sagen J

Combinations of intrathecal gamma-amino-butyrate receptor agonists and N-methyl-d-aspartate receptor antagonists in rats with neuropathic spinal cord injury pain.

• DOI: 10.1016/j.ejphar.2012.03.015
• 发表时间: 2012-05-15
• 期刊: EUROPEAN JOURNAL OF PHARMACOLOGY
• 影响因子: 5
• 作者: Hama, Aldric;Sagen, Jacqueline
• 通讯作者: Sagen, Jacqueline

Combined extrinsic and intrinsic manipulations exert complementary neuronal enrichment in embryonic rat neural precursor cultures: an in vitro and in vivo analysis.

• DOI: 10.1002/cne.22027
• 发表时间: 2009-07-01
• 期刊: The Journal of comparative neurology
• 作者: Furmanski O;Gajavelli S;Lee JW;Collado ME;Jergova S;Sagen J
• 通讯作者: Sagen J

Predifferentiated GABAergic neural precursor transplants for alleviation of dysesthetic central pain following excitotoxic spinal cord injury.

预分化 GABA 能神经前体移植用于缓解兴奋性毒性脊髓损伤后的感觉障碍中枢性疼痛。

• DOI: 10.3389/fphys.2012.00167
• 发表时间: 2012
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Lee,JeungWoon;Jergova,Stanislava;Furmanski,Orion;Gajavelli,Shyam;Sagen,Jacqueline
• 通讯作者: Sagen,Jacqueline