Matrix Metalloproteinases in Neuropathic Pain and Migraine: Friends, Enemies, and Therapeutic Targets

Figure 1

Changes in gelatinases (MMP-9 and MMP-2) and critical substrates during distinct phases of neuropathic pain induced by spinal nerve injury. In the first several days after spinal nerve injury in animal models (early phase), MMP-9 becomes upregulated in the dorsal root ganglion (DRG) neurons, where it is needed for IL-1β cleavage and activation. From the DRG neuronal soma, the gelatinase is transported to the dorsal horn central terminals, to activate microglia (via activation of a feedback loop between a mitogen-activated protein kinase, p38 MAPK, and IL-1β). In contrast, MMP-2 is induced and persists in DRG satellite cells and spinal cord astrocytes in the late phase of neuropathic pain generation (from a week to months after injury). This MMP is important in activating IL-1β, extracellular-regulated kinases (ERK), and astrocytes. A positive feedback also exists from IL-1β to both ERK and MMP-2 (which increases MMP-2 expression). Abundant evidence indicates that activation of microglia and astrocytes in the dorsal horn represents an essential amplification mechanism leading to neuropathic pain in the setting of spinal cord or nerve injury.