Pain Signaling and Plasticity Laboratory

Pain Signaling and Plasticity Laboratory

Lab Description

Chronic pain is a major health problem in the US and affects 100 million Americans, but the current treatments for chronic pain are inadequate. The current epidemic of opioid abuse is a result of lack of efficient pain medicine.  The main goal of the lab is to identify novel molecular and cellular mechanisms that underlie the genesis of chronic pain. We employ a multidisciplinary approach that covers in vitro, ex vivo, and in vivo electrophysiology, cell biology of glial cells, immune cells, and cancer cells, transgenic mice, and mouse behaviors of various sensory modalities after inflammation, nerve injury, and cancers. We believe that tackling the mechanisms of pain induction and resolution will lead to the development of novel therapeutics for preventing and treating chronic pain.

  1. Pain regulation by non-neuronal cells and inflammation: We investigate how non-neuronal cells such as glial cells, immune cells, stem cells, and cancer cells regulate pain via interactions with nociceptive neurons (nociceptors). We also investigate the interactions between inflammation, nociceptors, and immune cells in acute and chronic pain conditions.
    1. Chronic pain regulation by glial cells (microglia and astrocytes): We investigate how microglia and astrocytes in the spinal cord regulate the development and maintenance of choric pain. In particular, we focus on MAP kinase signaling (ERK, p38, JNK) in glial cells. We also examine sex-dependent signaling of microglial cells.
    2. Neuronal-glial interactions in chronic pain: We investigate (1) how neural signals 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.
    3. Neuroinflammation and chronic pain: We have demonstrated a critical role of neuroinflammation in the development and maintenance of chronic pain. We investigate how proinflammatory and anti-inflammatory cytokines regulate pathological pain. We also examine how nociceptors regulate neuroinflammation.
    4. Spinal cord synaptic plasticity as a driving force of chronic pain. We investigator how cytokines and chemokines (TNF-a, IL-1b, IL-17, CCL2, CXCL1, TGF-b) modulate excitatory and inhibitory synaptic transmission in chronic pain.
    5. Chronic pain control by bone marrow stem cells. We discovered that intrathecal injection of bone marrow stem cells produces long-term pain relief by releasing the anti-inflammatory cytokine TGF-b.
    6. Pain regulation by cancer cells. We investigate how melanoma cells mask pain by producing pain killers, such as PD-L1 to suppress nociceptive neuron activity. We investigate how immune therapy alters pain sensitivity.
  2. Molecular mechanisms of chronic pain:
    1. We investigate how neuronal toll-like receptors (TLR7, TLR3, TLR5) in primary sensory neurons regulate pain sensitivity.
    2. We investigate how secreted miRNAs (e.g., let-7b) regulate neuronal excitability via unconventional extracellular signaling to ion channels.
  3. Distinct mechanisms of pain and itch:
    1. We investigate how neuronal TLRs deferentially regulate pain and itch.
    2. We investigate whether miRNAs play distinct roles in pain and itch
  4. Resolution mechanisms and mediators of pain: One of the key mechanisms for the transition from acute pain to chronic pain is a failure in the resolution of acute pain and acute inflammation.
    1. We investigate how specialized pro-resolution mediators (SPMs), such as resolvins, neuroprotectins, and marresins, derived from omega-3 unsaturated fatty acids DHA and EPA, control pain by regulating inflammation, glial activation, TRP channels, and synaptic plasticity.
    2. We investigate whether SPM regulates pain via GPCR and b-arrestin 2 signaling. We investigate how b-arrestin 2 regulates the resolution of pain via arresting NMDA receptor function in the spinal cord.
  5. Pain and Autism. We found the autism gene SHANK3 is expressed in primary sensory neurons in mouse and human DRG tissue. We also found SHANK3 regulates the surface expression and function of TRPV1. We investigate peripheral and presynaptic mechanisms of pain dysregulation in autism.
  6. Development of novel pain therapeutics and diagnosis for the translation from bench to bed
    1. SPMs: We investigate how neuroprotectin D1 (NPD1) alleviates pain via specific receptors and distinct mechanisms.
    2. Sodium channels: We are developing and testing Nav1.7 monoclonal antibodies for the management of pain and itch.
    3. Stem cells: We are testing new methods that can enhance the homing and analgesic efficacy of bone marrow stem cells.
    4. Immune therapy: We propose that quantitative sensory test can be used to predict the target engagement of immune therapies (e.g., anti-PD-1 or anti-PD-L1 treatments).
    5. Neuromodulation: We investigate how neuromodulation such as electroacupuncture and auricular stimulation can produce long-term pain relief via regulation of neuro- inflammation.
    6. Human sensory neurons: We use human DRG neurons from donors to test mechanisms and treatments of clinical pain in “a dish”.

Ru-Rong Ji, PhDRu-Rong Ji, PhD
Laboratory Director
Professor
Chief of Pain Research
Basic Science Division
Duke Anesthesiology

Zhen-Zhong Xu, PhDZhen-Zhong Xu, PhD
Assistant Professor
Basic Science Division
Duke Anesthesiology

Muhammad Yawar J. Qadri, MDM. Yawar Qadri, MD, PhD
Assistant Professor
Pain Medicine Division
Duke Anesthesiology

Postdoctoral Fellows
Sangsu Bang, PhD
Qingjian Han, PhD
Changyu Jiang, PhD
Xin Luo, PhD

Visiting Fellow
Magumi Matsuda, MD, PhD

Students
Alexander Chamessian, MD – PhD Student
Yul Huh, Medical Student – PhD Student
Di Liu, Visiting PhD Student
Hao Luo, Visiting PhD Student
Linlin Zhang, Visiting PhD Student
Zilong Wang, Visiting PhD Student

Shirley Morton
Staff Assistant
919-681-4710

  1. Chen G, Kim YH, Li H, Luo H, Liu DL, Zhang ZJ, Lay M, Chang W, Zhang YQ, Ji RR. PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1. Nat Neurosci. 2017 May 22. doi: 10.1038/nn.4571. [Epub ahead of print]
  2. Han Q, Kim YH, Wang X, Liu D, Zhang ZJ, Bey AL, Lay M, Chang W, Berta T, Zhang Y, Jiang YH, Ji RR. SHANK3 deficiency impairs heat hyperalgesia and TRPV1 signaling in primary sensory neurons. Neuron, Dec 21;92(6):1279-1293, 2016
  3. Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Science, 2016, Nov 4; 354(6312):572-577.
  4. Chen G, Xie RG, Gao YJ, Xu ZZ, Zhao LX, Bang S, Berta T, Park CK, Lay M, Chen W, Ji RR. β-arrestin-2 regulates NMDA receptor function in spinal lamina II neurons and duration of persistent pain. Nat Commun. 2016 Aug 19;7:12531. doi: 10.1038/ncomms12531.
  5. Jiang BC, Cao DL, Zhang X, Zhang ZJ, He LN, Li CH, Zhang WW, Wu XB, Berta T, Ji RR, Gao YJ. CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5. J Clin Invest. 2016 Feb;126(2):745-61.
  6. Singh SK, Stogsdill JA, Pulimood NS, Dingsdale H, Kim YH, Pilaz LJ, Kim IH, Manhaes AC, Rodrigues WS Jr, Pamukcu A, Enustun E, Ertuz Z, Scheiffele P, Soderling SH, Silver DL, Ji RR, Medina AE, Eroglu C. Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin. Cell 2016 Jan 14;164(1-2):183-96.
  7. Xu ZZ, Kim YH, Bang S, Zhang Y, Berta T, Wang F, Oh SB, Ji RR. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nature Medicine. 2015 21(11):1326-3.
  8. Taves S, Berta T, Liu DL, Gan S, Chen G, Kim YH, Van de Ven T, Laufer S, Ji RR. Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord. Brain Behav Immun. 2015 Oct 19. pii: S0889-1591(15)30032-5.
  9. Chen G, Park CK, Xie RG, Ji RR. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-b secretion. J Clin Invest. 2015;125(8):3226-40.
  10. Sorge RE, Mapplebeck JCS, Rosen S, Beggs S, Taves S, Alexander JK, Martin LJ, Austin JS, Sotocinal SG, Chen D,  Yang M, Shi XQ, Huang H, Pillon NJ, Bilan PJ, Tu Y, Klip A, Ji RR, Zhang J, Michael W Salter MS,  Mogil JS. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. 2015, Nat Neurosci, 2015 Aug;18(8):1081-3.
  11. Yang Y, Li H, Li TT, Luo H, Gu XY, Lü N, Ji RR, Zhang YQ. Delayed Activation of Spinal Microglia Contributes to the Maintenance of Bone Cancer Pain in Female Wistar Rats via P2X7 Receptor and IL-18. J Neurosci. 2015 May 20;35(20):7950-63. *corresponding author.
  12. Zhang TC, Janik JJ, Peters RV, Chen G, Ji RR, Grill WM. Spinal Sensory Projection Neuron Responses to Spinal Cord Stimulation Are Mediated by Circuits Beyond Gate Control. J Neurophysiol. 2015 May 13:jn.00147.2015
  13. Loggia ML, Chonde DB, Akeju O, Arabasz G, Catana C, Edwards RR, Hill E, Hsu S, Izquierdo-Garcia D, Ji RR, Riley M, Wasan AD, Zürcher NR, Albrecht DS, Vangel MG, Rosen BR, Napadow V, Hooker JM. Evidence for brain glial activation in chronic pain patients. Brain. 2015, 138:604-615.
  14. Liu XJ, Zhang Y, Liu T, Xu ZZ, Park CK, Berta T, Jiang D, Ji RR. Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter. Cell Res. 2014 24:1374-1377.
  15. Ji RR, Xu ZZ, Gao YJ. Neuroinflammation drives chronic pain: emerging targets with pro- and anti-inflammatory roles. Nature Reviews Drug Discovery, 2014, 13:533-548.
  16. Lee JH, Park CK, Chen G, Han J, Xie RG, Liu T, Ji RR and Lee SY. A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief. Cell, 2014, 157:1393-404.
  17. Chen G, Park CK, Xie RG, Nedergaard M, Ji RR (2014) Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice. Brain, 2014, 137:2193-2209.
  18. 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.
  19. 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. 2014; 124:1173-86.
  20. Ji RR, Berta T, and Nedergaard M. Glia and pain: Is chronic pain and gliopathy? Pain, 2013, 154 Suppl 1: S10-28.
  21. Xu ZZ, Liu XJ, Berta T, Park CK, Lu N, Serhan CN, Ji RR. Neuroprotectin/protectin D1 protects neuropathic pain in mice after nerve trauma. Annals of Neurology, 2013, 74:490-495.
  22. 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 Ca(2+)-activated small conductance potassium channels. J Neurosci. 33:13425-30.
  23. Lu Y, Dong H, Gao Y, Gong Y, Ren Y, Gu N, Zhou S, Xia N, Sun YY, Ji RR, Xiong L. A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia. J Clin Invest. 2013, 123:4050-62.
  24. Liu T, Berta T, Xu ZZ, Park CK, Zhang L, Lü N, Liu Q, Liu Y, Gao YJ, Liu YC, Ma Q, Dong X, Ji RR. TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J Clin Invest. 2012, 122:2195-2207.

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, Pain Research
Co-Director, Center for Translational Pain Medicine

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

Contact Us

Duke University Medical Center
DUMC Box 3094
Office: 919-684-9387
Fax: 919-684-2411
Email: ru-rong.ji@dm.duke.edu

ChrisPain Signaling and Plasticity Laboratory