Jin M Chung
University Of Texas Medical Br Galveston
Project start date: 1993-12-01
Project end date: 2017-01-31
Sponsored Links Excellgen http://Excellgen.com
Mechanism Of Neuropathic Pain (CRPS)
Jin M Chung, Professor
University Of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555
Grant 2R01NS031680-09A1 from National Institute Of Neurological Disorders And Stroke IRG: SCS
Abstract: Complex regional pain syndrome (CRPS) is an especially difficult medical problem because it is a chronic disease affecting a patient s quality of life, often with no effective treatment. Therefore, it is important to understand the mechanisms of CRPS, thereby allowing new treatment paradigms to be developed, which is the long-term goal of this proposal. Using the spinal nerve ligation model, an extensively used rat model of CRPS (type II with major nerve injury), various aspects of the peripheral mechanisms of CRPS has been studied in the past, with support from the present grant. In the upcoming funding period of the present grant, however, the focus will be on spinal mechanisms of CRPS. The overall hypothesis is that spinal nerve injury induces a sustained elevated level of highly toxic free radicals, reactive oxygen species (ROS), in the spinal cord, leading in turn to central sensitization of dorsal horn neurons, which is the key underlying mechanism in CRPS. Four specific aims are proposed to test the following individual hypotheses 1) that spinal nerve ligation induces an elevated level of spinal ROS, 2) that the increased ROS are associated with central sensitization and behavioral signs of pain, 3) that an important mechanism of ROS-induced central sensitization is impairment of GABA function in the cord, and 4) that as time passes many dorsal horn neurons die due to extended exposure to ROS. The present proposal is to test these hypotheses using a multidisciplinary approach. Successful completion of these aims will not only uncover important spinal mechanisms of CRPS but may also lead to the development of new analgesic drugs based on free radical scavengers.
Project start date: 1993-12-01
Project end date: 2010-01-31
2R01NS031680-09A1 (2005): $349188
Jin M Chung, Professor
Neuroscience And Cell Biologyuniversity Of Texas Medical Br Galveston
301 University Blvd
galveston, Tx 77555
Grant 2R01NS031680-05A1 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: Adapted from ´s ) The long term goal of this proposal is to uncover mechanisms that underlie the disabling, painful neuropathic disease that often follows peripheral nerve injuries. In this regard, central sensitization plays a central role, and ectopic discharges from injured afferents initiate and maintain this central sensitization. Accordingly, the mechanisms that lead to ectopic discharges following peripheral axotomy are critically important and are thus the main focus of this proposal. An underlying hypothesis is that, if the mechanisms of impulse generation are understood, they can be better controlled, with a resultant reduction in central sensitization and thus in neuropathic pain. Four specific aims are proposed to unravel the mechanisms of ectopic impulse generation. The first is to show that there is a baseline component of ectopic discharge that is independent of activity in the sympathetic nervous system and an additive component that is dependent on sympathetic activity. This will be shown by in-vivo single dorsal root fiber recordings. The second aim is to show which sodium channel subtypes are up-regulated after nerve lesions, the assumption being that the up-regulated channels are important in impulse generation. This will be done with in-vivo and in-vitro electrophysiological recordings and molecular biological and immunohistochemical techniques. The third aim is to show which subtypes of adrenergic receptors are up-regulated, using the same techniques and assumptions as the second aim. The fourth aim is to determine the roles of purinergic and peptidergic systems in the generation of ectopic discharges. The effects of agonists and antagonists for ATP and neuropeptide Y, given either alone or in conjunction with adrenergic agents, on ectopic discharges in neuropathic rats will be examined using electrophysiological and pharmacological techniques
Keywords: alpha adrenergic receptor, hyperalgesia, nerve injury, peripheral nervous system disorder, sensory mechanism, sodium channel adenosine triphosphate, afferent nerve, disease model, dorsal root, electrophysiology, neuropathology, neuropeptide Y, purinergic receptor, spinal ganglion, sympathetic nervous system behavior test, immunocytochemistry, laboratory rat, sympathectomy
Project start date: 1993-12-01
Project end date: 2003-05-31
2R01NS031680-05A1 (1999): $223344
Grants awarded to Jin M Chung
PERIPHERAL AND CENTRAL SENSITIZATION IN PAIN
Jin M Chung, Professor
University Of Texas Medical Br Galveston, 301 University Blvd, Galveston, Tx 77555
Grant 5P01NS011255-34 from National Institute Of Neurological Disorders And Stroke
Abstract: This is a revised application for renewal of a long-standing Program Project. The focus of the Program Project has been on the role of the peripheral and central nervous system in pain mechanisms. Animal models of human pain states are used so that experimental manipulations can be employed to provide evidence for pathophysiological mechanisms of pain or potential improvements in therapy, hence translational capability would be heightened. An emerging concept in mechanisms underlying persistent pain is that elevated intracellular levels of reactive oxygen species (ROS) play a critical role in peripheral and central sensitization. The overall hypothesis of this PPG is that ROS themselves act as signaling molecules imposed upon the cell signaling pathways involved in sensitization processes. Three projects are proposed, each project is designed to reveal specific aspects of ROS involvement in central sensitization and persistent pain. Project 1 examines the role of ROS in central neuropathic pain. This project hypothesizes that chronic central neuropathic pain associated with spinal cord injury is composed of two components central and peripheral sensitization. The role of ROS in both of these components will be examined using in vivo and in vitro preparations in rats. Project 2 is concerned with the critical role of ROS in central sensitization in the spinal cord using a capsaicin induced hyperalgesia model in mice (including mutant mice). This project examines ROS metabolism in the spinal cord with the emphasis on the role of superoxide dismutase and the steps in which ROS sensitize dorsal horn neurons. Project 3 investigates the role of ROS in the sensitization of neurons in both the spinal cord and the central nervous system (amygdala) in visceral pain plasticity using a colitis pain model in rats. These projects will be interlinked by three cores Administrative, ROS Analytical, and Imaging Cores. Thus, sum of all projects interlinked by th
Project start date: 1974-02-01
Project end date: 2013-03-31
Budget start date: 1-APR-2010
Budget end date: 31-MAR-2011
5P01NS011255-34 (2010): $1125451
5P01NS011255-33 (2009): $1105595
SYMPATHETIC AND ADRENERGIC DEPENDENCY OF NEUROPATHIC PAIN
Jin M Chung, Professor
Institution:
Grant 2P01NS011255-22A10033 from National Institute Of Neurological Disorders And Stroke
Abstract: The long-term goal of this proposal is to uncover the mechanisms of disabling painful neuropathic disease, such as causalgia. Although exact mechanisms are not clear, two types of neuropathic pain can be distinguished based on sympathetic dependency sympathetically maintained pain (SMP) and sympathetically independent pain (SIP). In recent years, several animal models have been developed to investigate the mechanisms of neuropathic pain. Some of these models seem to represent SMP while others represent SIP. The present proposal uses these models to investigate the role of the sympathetic nervous system in neuropathic pain. Three specific aims are proposed. The first aim tests the hypothesis that proximal injury of a peripheral nerve induces SMP and distal injury induces SIP. This will be tested in 3 neuropathic pain models with injuries at different locations, using behavioral testing, immunohistochemical and electrophysiological methods. Second, to test the hypothesis that both SMP and SIP are maintained by a common mechanism of spinal sensitization caused by input of ectopic discharges arising from injured sensory neurons, correlations between ectopic discharges of injured afferent neurons and neuropathic pain behaviors in the 3 models will be made first and then the effects of blocking the spinal input from ectopic discharges on pain behaviors will be examined. Third, to test the hypothesis that certain pain states which are not influenced by denervation of sympathetic nerves (SIP) may still depend on adrenergic receptors, adrenergic dependency will be tested in the 3 models using behavioral tests and electrophysiological methods. Successful completion of this proposal is expected to accomplish 3 goals 1) to determine which type of injuries produce sympathetically dependent neuropathic pain; 2) to establish limitations of various animal models for neuropathic pain (which is helpful in choosing a model for experimental studies); and 3) to introduce the concept of "adrenergically maintained pain." Furthermore, the present proposal will have an important clinical implication in that it may lead to an improved diagnostic classification of neuropathic pain patients which in turn will help determine treatment strategies.
Keywords: alpha adrenergic receptor, pain, sympathetic nervous system, C fiber, afferent nerve, alpha antiadrenergic agent, behavioral habituation /sensitization, cell cycle, disease model, efferent nerve, electrophysiology, innervation, nerve injury, neuroanatomy, neuron, spinal ganglion, behavior test, immunocytochemistry, laboratory rat
Jin M Chung, Professor
University Of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555
Grant 5R01NS031680-04 from National Institute Of Neurological Disorders And Stroke IRG: NLS
Abstract: The long term goal of this proposal is to uncover the mechanism of the disabling painful neuropathic disease, such as causalgia, TO investigate the mechanisms of neuropathic pain, an animal model is developed by ligating the L5 and L6 spinal nerves of the rat unilaterally, This results in various behavioral signs of neuropathic pain that can be sen in human patients with sympathetically maintained pain (SMP), a particular type of neuropathic pain that is poorly understood. A series of hypotheses concerning the mechanisms that underlie SMP is formulated. To test the hypotheses, 6 specific aims are proposed. 1) To test whether SMP critically depends on ectopic discharges arising from the injured afferents, behavioral tests for neuropathic pain will be performed during conduction block of the activity of injured afferents. 2) To test whether the ectopic discharge are die to the development of abnormal adrenergic sensitivity by injured afferents, single unit activity will be recorded from dorsal root filaments of the injured segments and the effects of systemically applied adrenergic agonists and antagonist will be determined. 3) To test whether the ectopic discharges are due to sprouting of sympathetic postganglionic fibers and their newly formed synapses on sensory neurons, the noradrenergic fiber and putative synapses in the injured afferents will be examined using light and electron microscopic immunocytochemical labeling for antibody against tyrosine hydroxylase. 4) T test whether the ectopic discharges are due to the development of abnormal sympathetic activity, single unit activity will be recorded form postganglionic sympathetic fibers innervating the ligated spinal nerves. 5) To test whether evoke d pain (allodynia and hyperalgesia) is produced by inputs carried by intact (uninjured) afferents, behavioural tests for neuropathic pain will be performed during conduction block of the activity of intact afferents. 6) To test whether SMP is much more readily developed when the peripheral nerve is injured proximally as compared to a distal injury due to a more pronounced abnormality of the adrenergic system, adrenergic activity will be examined as proposed in Specific Aims 2-4 on two previously developed models which are produced by a distal injury. Accomplishing the specific aims will result in a better understanding of and an improved treatment for disabling neuropathic pain.
Keywords: hyperalgesia, nervous system neoplasm, peripheral nervous system disorder, sensory mechanism, sympathetic nervous system, afferent nerve, disease model, dorsal horn, ganglionic blocking agent, local anesthetic, nerve injury, neuronal guidance, norepinephrine, phentolamine, postganglionic fiber, sciatic nerve, spinal ganglion, sympathetic block, synaptogenesis, unspecific monooxygenase, behavior test, electron microscopy, immunocytochemistry, laboratory rat, sympathectomy
Project start date: 1993-12-01
Project end date: 1998-11-30
5R01NS031680-04 (1997): $166929
5R01NS031680-02 (1995): $193274
Neural Mechanisms Underlying Acupuncture Analgesia
Jin M Chung, Professor
Neuroscience And Cell Biologyuniversity Of Texas Medical Br Galveston, 301 University Blvd, Galveston, Tx 77555
Grant 5R01AT001474-04 from National Center For Complementary And Alternative Medicine IRG: IFCN
Abstract: DESCRIPTION () Acupuncture is appealing pain control technique in that it can evoke endogenous analgesic mechanisms by minimally invasive means. The mechanisms of acupuncture are not well understood, however, and one of the major problems impeding this understanding is a lack of proper experimental models. The present proposal describes a model of electroacupuncture (EA)- induced analgesia in ankle sprain pain. This model gives a repeatable and quantifiable index of persistent pain in the ankle joint and the preliminary data show that acupuncture at a remote site produces long-lasting analgesia in this model. This is shown by the finding the EA results in about 40% recovery of weight bearing by the hind limb with ankle sprain. This reproducibility and susceptibility to acupuncture will allow one to pursue the neural mechanisms of this phenomenon in considerably greater detail than has previously been possible. Four specific aims are proposed. Aim 1 is to investigate the origin and the fiber size group of afferent nerve fibers mediating EA analgesia using behavioral testing and electrophysiological techniques. Aim 2 is to test if EA induces NE release in the spinal cord by a descending system using pharmacological and neurochemical methods. Aim 3 is to test if ankle sprain induces central sensitization in the spinal cord as well as sensitization of peripheral nociceptors and EA reduces the level of central sensitization. Aim 4 is to test if the key CNS structures activated by EA is the anterior pretectal nucleus (APtN), which projects to brainstem noradrenergic cell groups to release NE in the spinal cord. Successful completion of this proposal will unveil important mechanisms underlying acupuncture analgesia in ankle sprain pain. This knowledge can then be applied to acupuncture analgesia in other forms of painful conditions, thereby gaining the insight to establish a maximally effective means of utilizing this endogenous analgesic system. An understanding of these mechanisms is necessary if acupuncture is to move into the mainstream of medical therapy.
Project start date: 2003-12-01
Project end date: 2007-11-30
5R01AT001474-04 (2007): $324393
Sponsored Links Excellgen http://Excellgen.com
Jin M Chung, Professor
University Of Texas Medical Br Galveston, 301 University Blvd, Galveston, Tx 77555
Abstract: Core A is the Administrative Core. It is directed by Dr. Jin Mo Chung, the Program Director. This Core supports all of the investigators in the Program Project. The core includes the services of two support personnel. Vicki Wilson is the Administrative Manager of the Program Project. She maintains communications with the Program Project faculty, organizes meetings, and collects information needed for Progress Reports. In part, Ms. Wilson also serves as the grant management specialist in that she allocates the budget to the different Projects and Cores and keeps accounts of expenditures. Dr. James J. Grady is an Associate Professor of Biostatistics in the Department of Preventive Medicine and Community Health at UTMB. He provides advice on experimental design and statistical analysis. His help with power analyses enables the group to predict the number of animals that will be needed for the planned experiments. In addition to routine administrative work, the Administrative Core is involved in educational programs for the Program Project group. These include mini courses and combined conferences between our Pain group and the UTMB Pain Clinic. Therefore, Core A plays central and integral part of this Program Project
5P01NS011255-34_9008 (2010): $93263
Mechanism Of Neuropathic Pain (CRPS)
Jin M Chung, Professor
University Of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555
Grant 5R01NS031680-11 from National Institute Of Neurological Disorders And Stroke IRG: SCS
Abstract: Complex regional pain syndrome (CRPS) is an especially difficult medical problem because it is a chronic disease affecting a patient s quality of life, often with no effective treatment. Therefore, it is important to understand the mechanisms of CRPS, thereby allowing new treatment paradigms to be developed, which is the long-term goal of this proposal. Using the spinal nerve ligation model, an extensively used rat model of CRPS (type II with major nerve injury), various aspects of the peripheral mechanisms of CRPS has been studied in the past, with support from the present grant. In the upcoming funding period of the present grant, however, the focus will be on spinal mechanisms of CRPS. The overall hypothesis is that spinal nerve injury induces a sustained elevated level of highly toxic free radicals, reactive oxygen species (ROS), in the spinal cord, leading in turn to central sensitization of dorsal horn neurons, which is the key underlying mechanism in CRPS. Four specific aims are proposed to test the following individual hypotheses 1) that spinal nerve ligation induces an elevated level of spinal ROS, 2) that the increased ROS are associated with central sensitization and behavioral signs of pain, 3) that an important mechanism of ROS-induced central sensitization is impairment of GABA function in the cord, and 4) that as time passes many dorsal horn neurons die due to extended exposure to ROS. The present proposal is to test these hypotheses using a multidisciplinary approach. Successful completion of these aims will not only uncover important spinal mechanisms of CRPS but may also lead to the development of new analgesic drugs based on free radical scavengers.
Keywords: dorsal horn, neuron, pain, DNA, GABA receptor, NMDA receptor, acid, analgesia, analgesic, apoptosis, base, behavior, behavioral habituation /sensitization, cell, cell death, central neural pathway /tract, cerebrospinal fluid, chronic disease /disorder, decarboxylase, electrophoresis, emotion, enzyme, excitatory aminoacid, free radical, free radical scavenger, gel, heat, high performance liquid chromatography, hyperalgesia, isomer, isoxazole, lead, liquid chromatography, measurement, microdialysis, model, necrosis, neoplasm /cancer, nerve injury, neuropeptide Y, oxide, oxygen, performance, play, quality of life, receptor, reduction, role, spinal cord, spinal nerve, sulfoxide, syndrome, synthetic enzyme, transferase
Project start date: 1993-12-01
Project end date: 2010-01-31
5R01NS031680-11 (2007): $331093
5R01NS031680-10 (2006): $340982
5R01NS031680-13 (2009): $331093
3R01NS031680-13S1 (2009): $49664
FUNCTIONAL CLASSIFICATION OF SOMATOSENSORY NEURONS
Jin M Chung
University Of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555
Grant 5P01NS011255-210027 from National Institute Of Neurological Disorders And Stroke
Abstract: Classifying neurons into functional subgroups is essential to the understanding of function in the central nervous system which has a large number of heterogeneous populations of neurons. In the somatosensory system, many attempts have been made to classify neurons both in the peripheral and central nervous system. However, none of them satisfactorily represent functions of the somatosensory system. The most important function of the somatosensory system is to transmit various sensory modalities and submodalities of somatic sensation. Therefore, the most useful functional classification of the somatosensory system would be grouping neurons by their potential contribution to sensory modalities. It is hypothesized that objective statistical treatment of the responses of somatosensory neurons to a set of stimuli which reflect sensory modalities will lead us to a new and functionally relevant classification scheme for somatosensory neurons. The goal of the present proposal is to test this hypothesis and thereby establish a new objective means of classifying somatosensory neurons. To achieve this goal, the following specific aims are proposed. First aim is to develop a "standard set of stimuli" to apply to the receptive fields of all the somatosensory neurons whose responses can then be used as the basis for a new classification scheme. And then, aims are directed to perform actual classification of somatosensory neurons of the rat and monkey at 4 different levels 1) primary afferent neurons; 2) dorsal horn neurons; 3) spinothalamic tract neurons; 4) somatosensory neurons in the thalamus. To achieve these aims, experiments will be performed in anesthetized rats and monkeys. Single cell recordings will be made from somatosensory neurons at the above 4 different levels. Multivariate statistical analysis, cluster analysis, will be performed on responses of neurons to the "standard set of stimuli" to classify neurons objectively. Achieving these specific aims will undoubtedly lead to a better understanding of sensory processing of somatosensory information in normal as well as in diseased states. This is the long term objective of the present proposal. Establishing an objective and functionally meaningful grouping of somatosensory neurons in normal animals will help us to interpret changes seen in diseased states.
Keywords: classification, cutaneous sensory nerve, nerve threshold, neuroanatomy, neuron, stimulus /response, brain pathway /tract, dorsal horn, mechanoreceptor, pain, somatic afferent nerve, spinal cord, spinal cord mapping, thalamus, thermoreception, Macaca fascicularis, computer processing of laboratory data, laboratory rat, microelectrode, single cell analysis, statistics /biometry
Sponsored Links Excellgen http://Excellgen.com
Jin M Chung, Professor
University Of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555
Grant 5R01NS031680-08 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: Adapted from s ) The long term goal of this proposal is to uncover mechanisms that underlie the disabling, painful neuropathic disease that often follows peripheral nerve injuries. In this regard, central sensitization plays a central role, and ectopic discharges from injured afferents initiate and maintain this central sensitization. Accordingly, the mechanisms that lead to ectopic discharges following peripheral axotomy are critically important and are thus the main focus of this proposal. An underlying hypothesis is that, if the mechanisms of impulse generation are understood, they can be better controlled, with a resultant reduction in central sensitization and thus in neuropathic pain. Four specific aims are proposed to unravel the mechanisms of ectopic impulse generation. The first is to show that there is a baseline component of ectopic discharge that is independent of activity in the sympathetic nervous system and an additive component that is dependent on sympathetic activity. This will be shown by in-vivo single dorsal root fiber recordings. The second aim is to show which sodium channel subtypes are up-regulated after nerve lesions, the assumption being that the up-regulated channels are important in impulse generation. This will be done with in-vivo and in-vitro electrophysiological recordings and molecular biological and immunohistochemical techniques. The third aim is to show which subtypes of adrenergic receptors are up-regulated, using the same techniques and assumptions as the second aim. The fourth aim is to determine the roles of purinergic and peptidergic systems in the generation of ectopic discharges. The effects of agonists and antagonists for ATP and neuropeptide Y, given either alone or in conjunction with adrenergic agents, on ectopic discharges in neuropathic rats will be examined using electrophysiological and pharmacological techniques.
Keywords: alpha adrenergic receptor, hyperalgesia, nerve injury, peripheral nervous system disorder, sensory mechanism, sodium channel, adenosine triphosphate, afferent nerve, disease /disorder model, dorsal root, electrophysiology, neuropathology, neuropeptide Y, purinergic receptor, spinal ganglion, sympathetic nervous system, behavior test, immunocytochemistry, laboratory rat, sympathectomy
Project start date: 1993-12-01
Project end date: 2005-01-31
5R01NS031680-08 (2002): $244056
5R01NS031680-07 (2001): $236947
5R01NS031680-06 (2000): $230046
Neural Mechanisms Underlying Acupuncture Analgesia
Jin M Chung, Professor
University Of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555
Grant 5R01AT001474-03 from National Center For Complementary And Alternative Medicine IRG: IFCN
Abstract: Acupuncture is appealing pain control technique in that it can evoke endogenous analgesic mechanisms by minimally invasive means. The mechanisms of acupuncture are not well understood, however, and one of the major problems impeding this understanding is a lack of proper experimental models. The present proposal describes a model of electroacupuncture (EA)- induced analgesia in ankle sprain pain. This model gives a repeatable and quantifiable index of persistent pain in the ankle joint and the preliminary data show that acupuncture at a remote site produces long-lasting analgesia in this model. This is shown by the finding the EA results in about 40% recovery of weight bearing by the hind limb with ankle sprain. This reproducibility and susceptibility to acupuncture will allow one to pursue the neural mechanisms of this phenomenon in considerably greater detail than has previously been possible. Four specific aims are proposed. Aim 1 is to investigate the origin and the fiber size group of afferent nerve fibers mediating EA analgesia using behavioral testing and electrophysiological techniques. Aim 2 is to test if EA induces NE release in the spinal cord by a descending system using pharmacological and neurochemical methods. Aim 3 is to test if ankle sprain induces central sensitization in the spinal cord as well as sensitization of peripheral nociceptors and EA reduces the level of central sensitization. Aim 4 is to test if the key CNS structures activated by EA is the anterior pretectal nucleus (APtN), which projects to brainstem noradrenergic cell groups to release NE in the spinal cord. Successful completion of this proposal will unveil important mechanisms underlying acupuncture analgesia in ankle sprain pain. This knowledge can then be applied to acupuncture analgesia in other forms of painful conditions, thereby gaining the insight to establish a maximally effective means of utilizing this endogenous analgesic system. An understanding of these mechanisms is necessary if acupuncture is to move into the mainstream of medical therapy.
Project start date: 2003-12-01
Project end date: 2007-11-30
5R01AT001474-03 (2006): $324393
5R01AT001474-02 (2005): $332200
1R01AT001474-01A1 (2004): $332200
Jin M Chung, Professor
University Of Texas Medical Br Galveston
301 University Blvd
galveston, Tx 77555
Grant 2P01NS011255-32A26155 from National Institute Of Neurological Disorders And Stroke IRG: NSD
Jin M Chung, Professor
Marine Biomedical Instituteuniversity Of Texas Medical Br Galveston
301 University Blvd
galveston, Tx 77555
Grant 5R01NS031680-03 from National Institute Of Neurological Disorders And Stroke IRG: NLS
Project start date: 1993-12-01
Project end date: 1997-11-30
5R01NS031680-03 (1996): $204240