Pain Signaling and Plasticity Laboratory

The researchers who work in Dr. Ji’s pain lab at GSRB-I: Sarah Taves, PhD; Temugin Berta, PhD; Chul-Kyu Park, PhD; Alexander Chamessian, MD/PhD student; Gang Chen, PhD; Rou-Gang Xie, PhD student; Zhen-Zhong Xu, PhD; Qingjian Han, PhD; Sangsu Bang, PhD; and Dr. Ru-Rong Ji

Lab Description

Chronic pain is a major health problem in the US affecting 100 million Americans, and the annual cost in the U.S. is over $600 billion. Unfortunately, the current treatments for chronic pain are inadequate. The main goal of the lab is to identify novel molecular and cellular mechanisms underlying the genesis of chronic pain, such as neuropathic pain after nerve trauma and chemotherapy and inflammatory pain after arthritis.

Specifically, we study neural and synaptic plasticity in chronic pain and investigate how glial cells such as microglia and astrocytes modulate synaptic plasticity in the spinal cord and brain stem. We investigate not only the induction mechanisms but also the resolution mechanisms of pain, which may underlie the transition from acute pain to chronic pain. We are also interested in distinct and similar mechanisms of pain and itch.

We employ multidisciplinary approaches that cover in vitro, ex vivo, and in vivo assays, electrophysiology, neuronal and glial cell biology, transgenic mice, and animal models and behaviors of pain and itch.

We hope that these studies are translational and will lead to the development of novel therapeutics for preventing and treating chronic pain in patients.

Major Research Interests

1. Neural and synaptic plasticity in the pain pathway

It is generally believed that chronic pain is an expression of neural plasticity in primary sensory neurons (peripheral sensitization) and spinal cord and cortical neurons (central sensitization). (1) We use patch clamp recordings in spinal cord or brain slices to investigate synaptic plasticity (e.g., EPSC, IPSC, LTP) in the pain circuitry after inflammation and nerve injury. (2) We examine how proinflammatory cytokines (e.g., TNF), chemokines (e.g., CCL2), and MAP kinases modulate spinal cord synaptic plasticity. (3) We also identify novel molecules (e.g., lipid mediators) that can normalize or reverse synaptic plasticity in chronic pain.

2. Pathogenesis of pain via neural-glial interactions

Glial cells such as microglia and astrocytes in the spinal cord and satellite glial cells in the dorsal root and trigeminal ganglia are highly activated in chronic pain conditions. Glial activation has been strongly implicated in the genesis of chronic pain. We investigate (1) how neural signals (e.g., neuronal activity), proteases (MMPs, caspases), and opioids activate glia, (2) how activation of MAP kinase pathways (ERK, p38, and JNK) in glial cells regulates the synthesis and release of glial mediators (cytokines, chemokines), (3) how glial hemichannels (e.g., connexin-43) control the release of glial mediators, and (4) how glial mediators regulate pain behaviors, neuronal excitability, and synaptic transmission.

3. Resolution of pain by anti-inflammatory and pro-resolution mediators

The lipid mediators resolvins (RvD1, RvD2, RvE1), neuroprotectins/protectins (NPD1/PD1), and marresins are derived from omega-3 unsaturated fatty acids (DHA, EPA) and exhibit potent anti-inflammation and pro-resolution actions in various animal models of diseases. We investigate how these lipid mediators control inflammatory and neuropathic pain by (1) modulating the activity of TRP channels, (2) normalizing synaptic plasticity, and (3) inhibiting glial activation and inflammation. (4) We also determine the downstream GPCR signaling in mediating the powerful actions of these lipid mediators.

4. Unconventional role of TLR signaling in primary sensory neurons

Toll-like receptors (TLRs) are normally expressed in immune cells and microglia to regulate innate immunity. We found that TLRs (e.g., TLR3 and TLR7) are also expressed by primary sensory neurons to modulate neuronal excitability. (1) We use single-cell PCR to investigate distinct expression patterns of different TLRs in different populations of DRG neurons. (2) We determine the functional coupling of TLRs with ion channels.  (3) We examine how TLRs regulate synaptic transmission in the spinal cord. (4) We search for endogenous ligands such as miRNAs of TLRs for neuronal activation.

5. Molecular mechanisms of itch

Itch and pain are closely related but distinct sensations and elicit scratching and withdrawal responses, respectively.  While acute itch is inhibited by scratching or painful stimuli, chronic itch is differently regulated by pain. Both histamine-dependent and independent mechanisms modulate acute itch, but chronic itch is often resistant to anti-histamine treatment. We investigate how TLRs regulate acute and chronic itch via neuronal and immune mechanisms.

Selected Publications

  1. Park CK, Xu ZZ, Berta, T, Han QJ, Liu XJ, Ji RR (2014)  Extracellular miRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron, 82:47-54.
  2. Lee JH, Park CK, Chen G, Han J, Xie RG, Liu T, Ji RR* and Lee SY* (2014). A monoclonal antibody that targets a NaV1.7 channel for painand itch relief. Cell, 157:1393-404. *co-corresponding authors.
  3. Berta T, Park CK, Xie RG, Xu ZZ, Lu N, Ji RR (2014)  Extracellular caspase-6 drives murine inflammatory pain via microglia TNF-a secretion. J Clin Invest. 124:1173-86.
  4. Ji RR, Xu ZZ, Gao YJ (2014) Emerging targets in neuroinflammation-driven chronic pain. Nature Reviews Drug Discovery, 13:533-48.
  5. Chen G, Park CK, Xie RG, Nedergaard M, Ji RR (2014) Connexin-43 induces chemokine release from spinal cordastrocytes to maintain late-phase neuropathic pain in mice. Brain, 137:2193-209.
  6. Liu XJ, Zhang Y, Liu T, Xu ZZ, Park CK, Berta T, Jiang D, Ji RR (2014) Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter.Cell Res. 2014 Aug 12. doi: 10.1038/cr.2014.106
  7. Xu ZZ, Liu XJ, Berta T, Park CK, Lü N, Serhan CN, Ji RR (2013) Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma. Ann Neurol.  74:490-5.
  8. Lu Y, Dong H, Gao Y, Gong Y, Ren Y, Gu N, Zhou S, Xia N, Sun YY, Ji RR, Xiong L (2013).  A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia. J Clin Invest. 123:4050-62.
  9. Pagadala P, Park CK, Bang S, Xu ZZ, Xie RG, Liu T, Han BX, Tracey WD Jr, Wang F, Ji RR (2013) Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: Involvement of Ca2+-activated small conductance potassium channels.J Neurosci. 14;33:13425-30.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. Liu T, Xu ZZ, Park CK, Berta T, Ji RR (2010). Toll-like receptor 7 mediates pruritis. Nature Neuroscience, 2010, 13:1460-1462.
  15. 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.
  16. Gao, Y.J., and Ji, R.R. (2010). Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacology & therapeutics 126, 56-68.
  17. 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.
  18. Ji RR, Gereau RW 4th, Malcangio M, Strichartz GR (2009) MAP kinase and pain. Brain Res Rev. 60:135-148.
  19. Kawasaki Y, Zhang L, Cheng JK, Ji RR (2008) Cytokine mechanisms of central sensitization: overlapping and distinct roles of proinflammatory cytokines IL-1b, IL-6, and TNF-a in regulating synaptic and neuronal activity. J Neurosci, 2008, 28:5189-5194.
  20. 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.

For a complete listing of publications click here (Ji RR, PubMed).

Ru-Rong Ji, PhD

Ru-Rong Ji, PhD

Distinguished Professor of Duke University
Professor of Anesthesiology
Professor of Neurobiology
Chief of Pain Research
Faculty, Center for Translational Pain Medicine
Duke University Medical Center
DUMC Box 3094
Office: 919-684-9387
Email: ru-rong.ji@dm.duke.edu

Visit the Duke Pain Program:
Basic, Translational, and Clinical Pain Research

Laboratory Staff Members

Zhen-Zhong Xu, PhD, Assistant Professor, NIH-funded investigator
Temugin Berta, PhD, Senior Research Associate
Alexander Chamessian, MD/PhD Student
Alessandra Martini, Visiting Student
Francesca Tang, Undergraduate Student
Gang Chen, PhD, Postdoctoral Fellow
Sangsu Bang, PhD, Postdoctoral Fellow
Qingjian Han, Ph.D. Postdoctoral Fellow
Sarah Whitley, PhD, Postdoctoral Fellow
Yong-Ho Kim, PhD, Postdoctoral Fellow
Kyoung Hwa Kwak, Postdoctoral Fellow
Wong-Seok Chang, PhD, Postdoctoral Fellow
Mathew Mauck, MD/PhD, Pain Fellow
Tong Liu, PhD, Visiting Fellow
Yong-Jing Gao, Visiting Fellow

Staff Assistant

Shirley Morton, 919-681-4710