Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain


Treatment of neuropathic pain, triggered by multiple insults to the nervous system, is a clinical challenge because the underlying mechanisms of neuropathic pain development remain poorly understood1,2,3,4. Most treatments do not differentiate between different phases of neuropathic pain pathophysiology and simply focus on blocking neurotransmission, producing transient pain relief. Here, we report that early- and late-phase neuropathic pain development in rats and mice after nerve injury require different matrix metalloproteinases (MMPs). After spinal nerve ligation, MMP-9 shows a rapid and transient upregulation in injured dorsal root ganglion (DRG) primary sensory neurons consistent with an early phase of neuropathic pain, whereas MMP-2 shows a delayed response in DRG satellite cells and spinal astrocytes consistent with a late phase of neuropathic pain. Local inhibition of MMP-9 by an intrathecal route inhibits the early phase of neuropathic pain, whereas inhibition of MMP-2 suppresses the late phase of neuropathic pain. Further, intrathecal administration of MMP-9 or MMP-2 is sufficient to produce neuropathic pain symptoms. After nerve injury, MMP-9 induces neuropathic pain through interleukin-1β cleavage and microglial activation at early times, whereas MMP-2 maintains neuropathic pain through interleukin-1β cleavage and astrocyte activation at later times. Inhibition of MMP may provide a novel therapeutic approach for the treatment of neuropathic pain at different phases.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Upregulation of MMP-9 in the DRG after SNL.
Figure 2: MMP-9 is both necessary and sufficient for neuropathic pain symptoms.
Figure 3: MMP-9 produces neuropathic pain through microglial activation and IL-1β signaling.
Figure 4: MMP-2 upregulation after SNL maintains neuropathic pain through IL-1β signaling and ERK activation in spinal astrocytes.


  1. Ji, R.R. & Strichartz, G. Cell signaling and the genesis of neuropathic pain. Sci. STKE 2004, reE14 (2004).

    PubMed  Google Scholar 

  2. Tsuda, M., Inoue, K. & Salter, M.W. Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia. Trends Neurosci. 28, 101–107 (2005).

    CAS  Article  Google Scholar 

  3. Woolf, C.J. & Mannion, R.J. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353, 1959–1964 (1999).

    CAS  Article  Google Scholar 

  4. Kehlet, H., Jensen, T.S. & Woolf, C.J. Persistent postsurgical pain: risk factors and prevention. Lancet 367, 1618–1625 (2006).

    Article  Google Scholar 

  5. Parks, W.C., Wilson, C.L. & Lopez-Boado, Y.S. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 4, 617–629 (2004).

    CAS  Article  Google Scholar 

  6. Chattopadhyay, S., Myers, R.R., Janes, J. & Shubayev, V. Cytokine regulation of MMP-9 in peripheral glia: Implications for pathological processes and pain in injured nerve. Brain Behav. Immun. 21, 561–568 (2007).

    CAS  Article  Google Scholar 

  7. Rosenberg, G.A. Matrix metalloproteinases in neuroinflammation. Glia 39, 279–291 (2002).

    Article  Google Scholar 

  8. Wang, X. et al. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J. Neurosci. 20, 7037–7042 (2000).

    CAS  Article  Google Scholar 

  9. Yong, V.W. Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat. Rev. Neurosci. 6, 931–944 (2005).

    CAS  Article  Google Scholar 

  10. Zhao, B.Q. et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat. Med. 12, 441–445 (2006).

    CAS  Article  Google Scholar 

  11. Kim, S.H. & Chung, J.M. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50, 355–363 (1992).

    CAS  Article  Google Scholar 

  12. Zhuang, Z.Y. et al. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J. Neurosci. 26, 3551–3560 (2006).

    CAS  Article  Google Scholar 

  13. Levin, J.I. et al. The discovery of anthranilic acid-based MMP inhibitors. Part 3: incorporation of basic amines. Bioorg. Med. Chem. Lett. 11, 2975–2978 (2001).

    CAS  Article  Google Scholar 

  14. Murphy, G. & Willenbrock, F. Tissue inhibitors of matrix metalloendopeptidases. Methods Enzymol. 248, 496–510 (1995).

    CAS  Article  Google Scholar 

  15. Coull, J.A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).

    CAS  Article  Google Scholar 

  16. Raghavendra, V., Tanga, F. & DeLeo, J.A. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J. Pharmacol. Exp. Ther. 306, 624–630 (2003).

    CAS  Article  Google Scholar 

  17. Tsuda, M. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783 (2003).

    CAS  Article  Google Scholar 

  18. Watkins, L.R., Milligan, E.D. & Maier, S.F. Glial activation: a driving force for pathological pain. Trends Neurosci. 24, 450–455 (2001).

    CAS  Article  Google Scholar 

  19. Jin, S.X., Zhuang, Z.Y., Woolf, C.J. & Ji, R.R. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J. Neurosci. 23, 4017–4022 (2003).

    CAS  Article  Google Scholar 

  20. Schonbeck, U., Mach, F. & Libby, P. Generation of biologically active IL-1β by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1β processing. J. Immunol. 161, 3340–3346 (1998).

    CAS  PubMed  Google Scholar 

  21. Samad, T.A. et al. Interleukin-1β-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410, 471–475 (2001).

    CAS  Article  Google Scholar 

  22. Sweitzer, S., Martin, D. & DeLeo, J.A. Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience 103, 529–539 (2001).

    CAS  Article  Google Scholar 

  23. Sung, C.-S. et al. Inhibition of p38 mitogen-activated protein kinase attenuates interleukin-1β-induced thermal hyperalgesia and inducible nitric oxide synthase expression in the spinal cord. J. Neurochem. 94, 742–752 (2005).

    CAS  Article  Google Scholar 

  24. Clark, A.K. et al. Rapid co-release of interleukin 1β and caspase 1 in spinal cord inflammation. J. Neurochem. 99, 868–880 (2006).

    CAS  Article  Google Scholar 

  25. Inoue, M. et al. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nat. Med. 10, 712–718 (2004).

    CAS  Article  Google Scholar 

  26. Zhuang, Z.Y., Gerner, P., Woolf, C.J. & Ji, R.R. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 114, 149–159 (2005).

    Article  Google Scholar 

  27. Dworkin, R.H. et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch. Neurol. 60, 1524–1534 (2003).

    Article  Google Scholar 

  28. Tan, P.H., Yang, L.C., Shih, H.C., Lan, K.C. & Cheng, J.T. Gene knockdown with intrathecal siRNA of NMDA receptor NR2B subunit reduces formalin-induced nociception in the rat. Gene Ther. 12, 59–66 (2005).

    CAS  Article  Google Scholar 

  29. Chen, S. et al. Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss. Nat. Neurosci. 6, 1186–1193 (2003).

    CAS  Article  Google Scholar 

Download references


The work was supported in part by US National Institutes of Health grants R01-DE17794, R01-NS54362 and TW7180 to R.-R.J. and R01-NS37074, R01-NS48422, R01-NS56458, P01-NS55104 and P50-NS10828 to E.H.L. P.-H.T. was supported by a grant from E-DA Hospital/I-Shou University, Taiwan. We thank T. Kohno (Niigata University, Japan) for providing FR167653 compound and Q. Ma (Harvard Medical School) for critical reading of the manuscript.

Author information

Authors and Affiliations



Y.K. performed behavioral and immunohistochemical experiments; Z.-Z.X. conducted western blotting, DRG culture and zymography studies; X.W. performed zymography studies and contributed to project development; J.Y.P. conducted behavioral studies; Z.-Y.Z. conducted initial behavioral and histochemical studies; P.-H.T. designed siRNAs and initially tested MMP-9 siRNA; Y.-J.G. conducted ELISA studies and prepared astrocyte cultures; K.R. and G.C. contributed to electron microscopy studies; E.H.L. developed the project and provided critical review and comments on the manuscript. R.-R.J. developed and supervised the project, designed all the experiments, conducted some data analysis and prepared the manuscript.

Corresponding author

Correspondence to Ru-Rong Ji.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Methods, Supplementary Results, Supplementary Discussion (PDF 964 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kawasaki, Y., Xu, ZZ., Wang, X. et al. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 14, 331–336 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing