Chronic or persistent pain is a difficult medical problem which affects millions of people in the U.S. because of no effective treatment. Therefore it is important to understand the mechanisms of persistent pain thereby allowing new treatment paradigms to be developed. An important discovery during the last few decades is that persistent pain is an abnormal state of the nervous system where neurons in the periphery and the central nervous system are sensitized, called as peripheral and central sensitization, respectively. A recent emerging concept in persistent pain is that elevated levels of spinal reactive oxygen species (ROS) play a critical role in central sensitization. The focus of this proposal is the role of ROS in capsaicin induced secondary hyperalgesia due to central sensitization. The overall hypothesis is that increased production of mitochondrial superoxides in neurons in response to excessive nociceptive inputs elevates ROS in the spinal cord. The elevated ROS then activate protein kinases, leading to increased NMDA receptor activation and thus central sensitization.
Four specific aims are proposed to test the following hypotheses in the mouse: 1) elevation of spinal ROS is critical for production of capsaicininduced secondary hyperalgesia, thus removing ROS reduces pain;2) elevation of spinal ROS is due to increased production of superoxides in neurons in response to nociceptive afferent inputs;3) superoxide dismutase (SOD) is a major mechanism for reducing spinal ROS effects;and 4) elevated spinal ROS will sensitize dorsal horn neurons by activating protein kinases, leading to enhanced phosphorylation of NMDA receptors and thus central sensitization. The present proposal will test these hypotheses using a multidisciplinary approach. Successful completion of these aims will uncover important spinal mechanisms of persistent pain and may lead to the development of new analgesic drugs based on free radical scavengers.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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University of Texas Medical Br Galveston
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Young, E E; Bryant, C D; Lee, S E et al. (2016) Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test. Genes Brain Behav 15:604-15
Carter, Michael W; Johnson, Kathia M; Lee, Jun Yeon et al. (2016) Comparison of Mechanical Allodynia and Recovery of Locomotion and Bladder Function by Different Parameters of Low Thoracic Spinal Contusion Injury in Rats. Korean J Pain 29:86-95
Hammell, D C; Zhang, L P; Ma, F et al. (2016) Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. Eur J Pain 20:936-48
Ji, Guangchen; Li, Zhen; Neugebauer, Volker (2015) Reactive oxygen species mediate visceral pain-related amygdala plasticity and behaviors. Pain 156:825-36
Neugebauer, Volker (2015) Amygdala pain mechanisms. Handb Exp Pharmacol 227:261-84
Yuan, Su-Bo; Ji, Guangchen; Li, Bei et al. (2015) A Wnt5a signaling pathway in the pathogenesis of HIV-1 gp120-induced pain. Pain 156:1311-9
Ji, Guangchen; Neugebauer, Volker (2014) CB1 augments mGluR5 function in medial prefrontal cortical neurons to inhibit amygdala hyperactivity in an arthritis pain model. Eur J Neurosci 39:455-66
Medina, Georgina; Ji, Guangchen; Grégoire, Stéphanie et al. (2014) Nasal application of neuropeptide S inhibits arthritis pain-related behaviors through an action in the amygdala. Mol Pain 10:32
Hassler, Shayne N; Johnson, Kathia M; Hulsebosch, Claire E (2014) Reactive oxygen species and lipid peroxidation inhibitors reduce mechanical sensitivity in a chronic neuropathic pain model of spinal cord injury in rats. J Neurochem 131:413-7
Gwak, Young S; Hassler, Shayne E; Hulsebosch, Claire E (2013) Reactive oxygen species contribute to neuropathic pain and locomotor dysfunction via activation of CamKII in remote segments following spinal cord contusion injury in rats. Pain 154:1699-708

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