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

Abstract

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.

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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.

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Acknowledgements

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.

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Authors and Affiliations

Authors

Contributions

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.

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

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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). https://doi.org/10.1038/nm1723

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