Techniques and Approaches

  • Animal Models
    • Injury associated neuropathic pain (mouse, rat)
    • Mouse model of temporomandibular joint disorder (TMD)
    • Diabetic neuropathic pain (rat)
    • Inflammatory pain (mouse, rat)
    • Mouse model for autoimmune peripheral neuropathy
    • Mouse model of specific diet induced abnormal pain behavior
  • Behavioral Testing
    • Von Frey test
    • Acetone test
    • Hot plate/Plantar test
    • Rota Rod test
  • In Vivo Pharmacology
    • Drug administration via intraperitoneal, intravenous, intrathecal, subcutaneous, oral gavage routes
    • Validation of drug targets in rodent animal models
  • Immunohistochemistry
    • Regular fluorescent microscopy
    • Confocal microscopy
    • Sophisticated image analysis software
  • Tissue-based cellular, molecular and biochemistry analysis
    • Flow cytometry
    • Real time PCR
    • Western Blot
    • ELISA
    • Luminex Assay
  • In vitro experiments
    • Primary cell culture
    • Cell sorting

Theme 1: The involvement of the immune system in chronic pain

Uncovering the impact of spinal microglia activation in neuropathic pain

We have pioneered in the roles of spinal microglia in neuropathic pain. Our results demonstrated that following an injury to the peripheral nerve, spinal microglia became activated. Chemokine MCP-1, released by damaged neurons, is responsible for triggering the microglial activation. By using genetic and pharmacological approaches, we reported that both resident microglia and recruited circulating macrophages contribute to the development of neuropathic pain associated with injury.

Selected publications

  1. Y Yao, S Echeverry, XQ Shi, M Yan, QZ Yang, GYF Wang, J Chambon, YC Wu, KY Fu, Y De Koninck, J Zhang (2016) Dynamics of spinal microglia repopulation following an acute depletion. Scientific Reports 6:22839
  2. J Zhang, XQ Shi, S Echeverry, JS Mogil, Y De Koninck, S Rivest (2007) Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J of Neuroscience 27(45): 12396-12406
  3. J. Zhang, Y. De Koninck (2006). Spatial and temporal relationship between MCP-1 expression and spinal microglial activation following peripheral nerve injury. J.Neurochem. 97, 772-783
Understanding the roles of macrophages in injured nerves to the development of neuropathic pain

Macrophages play a crucial role in the process of degeneration/regeneration following an injury to the peripheral nerve. Our results indicated that depleting macrophages reduced injury induced-hypersensitivity. We further revealed that macrophages in the injured nerves exhibit heterogeneity. We identified subsets of macrophages responsible for neuropathic pain behavior.

Selected publications

  1. S Echeverry, YC WU and J Zhang (2013) Selectively reducing cytokine/chemokine expressing macrophages in injured nerves impairs the development of neuropathic pain Experimental Neurology 240:205-18
  2. SH Lee and J Zhang (2012) Heterogeneity of macrophages in injured trigeminal nerves: Cytokine/chemokine expressing vs. phagocytic macrophages, Brain, Behavior and Immunity 26: 891-903
Demonstrating the importance of neural barriers along the pain signaling pathway in neuropathic pain

Nerve injury triggered long lasting disruption of the blood nerve barrier (BNB) and the blood spinal cord barrier (BSCB), which resulted in the infiltration of immune cells and extravasation of pro-nociceptive molecules. Our results demonstrated that enhanced pain sensitivity could be driven by blood-borne derived molecules bypassing neural barriers at both peripheral and central sites. The findings have additional implication. Since through the same mechanism, pharmacological agents could be permitted selective access to injured nerves, without affecting healthy ones, a new strategy for drug discovery.

Selected publications

  1. TKY Lim, XQ Shi, HC Martin, H Huang, G Luheshi, S Rivest, J Zhang (2014) Blood-nerve barrier dysfunction contributes to the generation of neuropathic pain and allows targeting of injured nerves for pain relief Pain, 2014, 2
  2. S Echeverry, XQ Shi, S Rivest , J Zhang (2011) Peripheral nerve injury alters blood spinal cord barrier functional and molecular integrity through a selective inflammatory pathway J of Neuroscience 31(30):10819-28
Providing evidence that anti-inflammation can be a useful strategy to treat neuropathic pain

Our findings showed that anti-inflammatory treatment with pharmacological and genetic manipulation of immune/glial cell activities can alleviate neuropathic pain. Following targets/drugs have been investigated in our rodent experimental neuropathic pain models: Statins, TGF-β1, CCR2, CCR5, TLR2, IL-1β, TNF-α and CSFR-1.

Selected publications

  1. SSV Padi, Xiang Q Shi, Yuan Q Zhao, Michael R. Ruff, Noel Baichoo, Candace B. Pert, and Ji Zhang (2012) Attenuation of Rodent Neuropathic Pain by an Orally Active Peptide, RAP-103, which Potently Blocks CCR2 and CCR5 Mediated Monocyte Chemotaxis and Inflammation Pain 153(1): 95-106
  2. XQ Shi, T Lim, YQ Zhao, J Zhang (2011) Statins alleviate experimental nerve injury induced neuropathic pain Pain 152(5):1033-43

Theme 2: Molecular and cellular mechanisms of autoimmune peripheral neuropathy

We reported that T cell co-stimulation factor B7.2 (L31) mice spontaneously develop neurological disorders. These mice mimic many clinical and pathological signatures of Guillain Barre Syndrome in human, providing an excellent opportunity to explore molecular and cellular mechanisms underlying disease pathogenesis. We are investigating 1) the critical roles of CD8 T cells and macrophages in disease pathogenesis; 2) the mechanisms underlying viral infection and injury associated autoimmune peripheral neuropathy.

Selected publications

  1. M Yang, C Peyret, XQ Shi, N Siron, JH Jang, S Wu, S Fournier and J Zhang (2015) Evidence from human and animal studies: Pathological roles of CD8+ T cells in autoimmune peripheral neuropathies. Frontiers in Immunology Oct 15; 6:532.
  2. M Yang, A Rainone, XQ Shi, S Fournier and J Zhang (2014) A New Animal Model of Spontaneous Autoimmune Peripheral Polyneuropathy: Implications for Guillain Barré Syndrome Acta Neuropathologica Communications 2014, 2:5

Theme 3: The influence of dietary habit and gut microbiota in pain behavior

We observed that high fat diet induced obese mice developed hypersensitivity to mechanical and cold stimulation, which was associated with spinal microglia activation. The impact of some other specific diet, e.g, high salt diet on pain behavior is currently under investigation. We are also intrigued to explore the potential role of gut microbiota in pain behavior.

Selected publications

  1. SH Lee, YS Wu, XQ Shi, J Zhang (2015) Characteristics of spinal microglia in aged and obese mice: potential contributions to impaired sensory behavior. Immunity & Ageing. Nov 24; 12:22.