Next, we showed that NOV regulates MMP-2 and MMP-9 in vivo and that these regulations are associated with altered pain intensity. In CFA rats, the siRNAmediated knockdown of NOV led to a specific upregulation of MMP-9 in the DRG and MMP-2 in the DHSC (and CCL2 in the DRG, **data** not shown), consistent with our in vitro data. Remarkably, endogenously produced NOV depletion resulted in increased tactile hypersensitivity. The compatible pattern of MMP-2/-9 and NOV expression at the late phase of inflammatory pain further raises the possibility that NOV reduction could specifically lead to transient MMP-9 induction in the DRG and a persistent increase of MMP-2 expression in the spinal cord, thereby contributing to the maintenance of pain. Admittedly, NOV is likely to act in concert with other specific partners of a given neuroinflammatory environment to modulate MMP-2/-9 expression. This is supported by our **data** showing NOV modulation of cytokine activities in vitro and cytokines induction at a late phase of inflammatory pain. In addition, NOV reduction at a late phase of the development of inflammatory pain contrasts with the early development of pain hypersensitivity indicating that NOV might not be involved in the early stage of pain induction but be required at a later precise time slot during pain pathogenesis. Even though the NOV-null mouse has been generated recently, its nervous system phenotype has not yet been reported. The NOV-null mouse shows normal development but enhanced neointimal hyperplasia in response to endothelial injury [48]. Our **data** thus reinforce the idea that NOV is highly important in tissue homeostasis especially in case of injury [24] and further highlight the interest of investigating pain symptoms in NOV-null mice. These findings indicate that endogenous NOV may have an important function in limiting the deleterious effects of pro-inflammatory cytokines particularly on MMPs expression in the nociceptive system.