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 understood^{1, 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-1 cleavage and microglial activation at early times, whereas MMP-2 maintains neuropathic pain through interleukin-1 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.

1. Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Medical Research Building, Room 604, Boston, Massachusetts 02115, USA.
2. Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, 149 13^th Street, Charlestown, Massachusetts 02129, USA.
3. Division of Neuroscience, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
4. These authors contributed equally to this study.

Correspondence to: Ru-Rong Ji¹ e-mail: rrji@zeus.bwh.harvard.edu

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