Tissue injury-induced inflammatory pain is characterized by mechanical allodynia and heat hyperalgesia that are mediated by distinct mechanisms. In particular, persistent pain is characterized by mechanical allodynia. Our incomplete understanding of how mechanical allodynia is maintained hinders the effective treatment of chronic pain. Current pain research focuses primarily on neuronal cells and neural networks. Less is known about the importance of glial cells and the glial network, in particular the astroglial network in chronic pain conditions. The overall goal of this application is to investigate the role of spinal astrocytes and astroglial network in regulating mechanical allodynia during persistent inflammatory pain. Our strategy is to target signaling molecules that are specifically expressed and induced in spinal astrocytes after tissue injury. c-Jun N-terminal kinase (INK) is a member of MAP kinase family. Our pilot studies have shown that (a) CFA inflammation induces JNK activation exclusively in spinal astrocytes, (b) a peptide INK inhibitor blocks maintenance phase of mechanical allodynia without affecting heat hyperalgesia, and (c) the astroglial gap junction protein connexin-43 (Cx43) is upregulated by inflammation and a gap junction blocker suppresses mechanical allodynia but not heat hyperalgesia. Our central hypothesis is that JNK is a critical signaling molecule in spinal astrocytes, and that persistent JNK activation by inflammation makes important contribution to the maintenance of mechanical allodynia via an astroglial network. This hypothesis will be tested using the methods of behavioral testing, immunohistochemistry, in situ hybridization, Western blotting, and a kinase assay. Cellular localization of signaling molecules will be examined by double staining of immunofluorescence and double staining of fluorescence in situ hybridization and immunofluorescence. We will use the CFA inflammation model to accomplish the following three specific aims: (1) to establish that inflammation induces persistent JNK activation in spinal astrocytes and that this activation is essential for the maintenance of mechanical allodynia, (2) to define the importance of Cx43-mediated spinal astroglial network for persistent mechanical allodynia, and (3) to explore molecular and cellular mechanisms by which spinal JNK and the astroglial network regulate mechanical allodynia. These proposed studies will (a) identify novel molecular and cellular mechanisms underlying the maintenance of mechanical allodynia, (b) document important roles of spinal astrocytes and the glial network for chronic pain, and (c) reveal spinal JNK pathway as a new target for the treatment of chronic pain. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS054932-01A1
Application #
7208416
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2007-01-15
Project End
2010-12-31
Budget Start
2007-01-15
Budget End
2007-12-31
Support Year
1
Fiscal Year
2007
Total Cost
$359,188
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Liu, Chien-Cheng; Gao, Yong-Jing; Luo, Hao et al. (2016) Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions. Sci Rep 6:34356
Xu, Zhen-Zhong; Berta, Temugin; Ji, Ru-Rong (2013) Resolvin E1 inhibits neuropathic pain and spinal cord microglial activation following peripheral nerve injury. J Neuroimmune Pharmacol 8:37-41
Xu, Zhen-Zhong; Liu, Xing-Jun; Berta, Temugin et al. (2013) Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma. Ann Neurol 74:490-5
Berta, T; Liu, Y-C; Xu, Z-Z et al. (2013) Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1? and ERK signaling in the spinal cord of mice. Neuroscience 247:376-85
Berta, Temugin; Liu, Tong; Liu, Yen-Chin et al. (2012) Acute morphine activates satellite glial cells and up-regulates IL-1? in dorsal root ganglia in mice via matrix metalloprotease-9. Mol Pain 8:18
Tan, P H; Gao, Y J; Berta, T et al. (2012) Short small-interfering RNAs produce interferon-?-mediated analgesia. Br J Anaesth 108:662-9
Liu, Tong; Ji, Ru-Rong (2012) Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice. Neurosci Bull 28:145-54
Liu, Tong; Gao, Yong-Jing; Ji, Ru-Rong (2012) Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull 28:131-44
Liu, Yen-Chin; Berta, Temugin; Liu, Tong et al. (2012) Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in mice. Mol Pain 8:19
Ji, Ru-Rong; Xu, Zhen-Zhong; Strichartz, Gary et al. (2011) Emerging roles of resolvins in the resolution of inflammation and pain. Trends Neurosci 34:599-609

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