Sensory Plasticity Laboratory

Chronic pain is a major health problem in the US affecting 100 million Americans, but the current treatments for chronic pain are inadequate. The main goal of the lab is to identify novel molecular and cellular mechanisms that underlie the genesis of chronic pain. Recently, we also began to explore the mechanisms underlying the resolution of acute pain, and these mechanisms are responsible for the transition from acute pain to chronic pain.  Very recently, we became interested in distinct molecular mechanisms of pain and itch. We employ a multidisciplinary approach that covers in vitro, ex vivo, and in vivo electrophysiology, neuronal and glial cell biology, transgenic mice, and behaviors. We believe that tackling the mechanisms of pain induction and resolution will lead to the development of novel therapeutics for chronic pain and itch.

Major research interests of the lab:

Pathogenesis of pain via neural-glial interactions: We investigate (1) how neural signals (e.g., electrical activity and release of proteases) in primary sensory neurons cause the activation of glial cells (microglia and astrocytes) in the spinal cord after tissue and nerve injury, and (2) how glia mediators (e.g., cytokines and chemokines) modulate spinal cord synaptic transmission. We have demonstrated that distinct activation MAPK signaling pathways (ERK, p38, and JNK) in spinal cord microglia and astrocytes is critical for the development of neuropathic pain. We have also demonstrated that proinflammatory cytokines and chemokines (e.g., TNF-a, IL-1b, and MCP-1) can powerfully modulate synaptic transmission in the spinal cord, by enhancing excitatory synaptic transmission and suppressing inhibitory synaptic transmission.

Resolution of pain by anti-inflammatory and pro-resolution mediators: We investigate how lipid mediators, such as resolvins and neuroprotectins, and marresins, derived from omega-3 unsaturated fatty acids control pain by (1) blocking TRP channels, (2) resolving synaptic plasticity, and (3) inhibit inflammation and glial activation. We have shown that resolvins are among the most potent inhibitors for inflammatory pain and TRP channels. We also determine the down-stream GPCR signaling that mediates the potent actions of these lipid mediators.

Molecular mechanisms of itch: We investigate how toll-like receptors (TLRs) and oxidative stress regulate acute and chronic itch. We found an unconventional and non-transcriptional role of TLRs: TLRs (e.g., TLR3 and TLR7), expressed by primary sensory neurons, contribute to itch by modulating excitability of primary sensory neurons and spinal cord synaptic transmission. We now determine the functional coupling of TLRs and ion channels.

Representative publications:

1. Liu T, Berta T, Xu ZZ, Park CK, Zhang L, Lu N, Liu Q, Liu Y, Gao YJ, Liu YC, Ma Q, Dong X, Ji RR (2012) TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J Clin Invest, 122:2195-207.
2. Park CK, Lü N, Xu ZZ, Liu T, Serhan CN, Ji RR (2011) Resolving TRPV1- and TNF-alpha-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J Neurosci, 31:15072-85.
3. Park CK, Xu ZZ, Liu T, Lü N, Serhan CN, Ji RR (2011) Resolvin D2 is a potent endogenous inhibitor for TRPV1/A1, inflammatory pain, and spinal cord synaptic plasticity: Distinct roles of Resolvin D1, D2, and E1. J Neurosci, 31(50):18433-8.
4. Ji RR, Xu ZZ, Strichartz G, Serhan CN (2011) Emerging roles of resolvins in the resolution of inflammation and pain. Trends Neurosci. 34:599-609.
5. Liu T, Xu ZZ, Park CK, Berta T, Ji RR (2010). Toll-like receptor 7 mediates pruritis. Nature Neuroscience, 2010, 13:1460-1462.
6. Xu ZZ, Zhang L, Liu T, Park JY, Berta T,  Yang R，Serhan CN, Ji RR (2010) Resolvins attenuate inflammatory pain via central and peripheral actions. Nature Medicine, 16:592-597.
7. Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ, Park JY, Lind AL, Ma Q, Ji RR (2009) JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci, 2009, 29:4096-108.
8. Ji RR, Gereau RW 4th, Malcangio M, Strichartz GR (2009) MAP kinase and pain. Brain Res Rev. 60:135-148.
9. Kawasaki Y, Zhang L, Cheng JK, Ji RR (2008) Cytokine mechanisms of central sensitization: overlapping and distinct roles of proinflamamtory cytokines IL-1b, IL-6, and TNF-a in regulating synaptic and neuronal activity. J Neurosci, 2008, 28:5189-5194.
10. Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH, Gao YJ, Roy K, Corfas G, Lo EH, Ji RR (2008) Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nature Medicine, 14:331-336.

Ru-Rong Ji, PhD

Professor
Chief of Pain Research
Department of Anesthesiology
Duke University Medical Center
DUMC Box 3094
GSRB-I, Room 1027A
595 LaSalle Street
Durham, NC 27710
Office: 919-684-9387
Fax: 919-684-2411
Email: ru-rong.ji@dm.duke.edu

Laboratory Staff Members:

Zhen-Zhong Xu, PhD, Research Associate, Sr.
Tong Liu, PhD, Postdoctoral Fellow
Temugin Berta, PhD, Postdoctoral Fellow
Chul Kyu Park, PhD, Postdoctoral Fellow
Xing-Jun Liu, PhD, Postdoctoral Fellow
Gang Chen, PhD,  Postdoctoral Fellow

Other Related Members:

Thomas J. Van de Ven, MD, PhD, Assistant Professor
Shirley Morton, Lab/Staff Assistant