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 1-4 . 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 after nerve injury require different matrix metalloproteinases (MMPs). After spinal nerve ligation, MMP-9 shows a rapid and transient upregulation in injured 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 via an intrathecal route inhibits the early phase of neuropathic pain, whereas inhibition of MMP-2 suppresses late phase of neuropathic pain. Further, intrathecal administration of MMP-9 or MMP-2 is sufficient to produce neuropathic pain symptoms. Following nerve injury, MMP-9 induces neuropathic pain through interleukin-1β cleavage and microglia 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.Matrix metalloproteinases (MMPs) are widely implicated in inflammation and tissue remodeling associated with various neurodegenerative diseases through the cleavage of the extracellular matrix proteins, cytokines, and chemokines 5-10 . We hypothesized that neuropathic pain and neuroinflammation may share similar mechanisms. Therefore, we set out to study the roles of the two major gelatinases MMP-2 and MMP-9, in the pathophysiology of neuropathic pain using a well-characterized animal model of L5 spinal nerve ligation (SNL) 11 .Since nerve injury-induced changes in the dorsal root ganglion (DRG) are essential for the generation of neuropathic pain 1 , we examined gelatinase activity in injured (L5) DRGs.

Current analgesics predominately modulate pain transduction and transmission in neurons and have limited success in controlling disease progression. Accumulating evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of glial cells and production of inflammatory mediators in the peripheral and central nervous system, has an important role in the induction and maintenance of chronic pain. This review focuses on emerging targets such as chemokines, proteases and the Wnt pathway that promote spinal cord neuroinflammation and chronic pain. It also highlights the anti-inflammatory and pro-resolution lipid mediators that act on immune cells, glial cells and neurons to resolve neuroinflammation, synaptic plasticity and pain. Targeting excessive neuroinflammation could offer new therapeutic opportunities for chronic pain and related neurological and psychiatric disorders.