Abstract
BackgroundSustained neuroinflammation strongly contributes to the pathogenesis of pain. The clinical challenge of chronic pain relief led to the identification of molecules such as cytokines, chemokines and more recently matrix metalloproteinases (MMPs) as putative therapeutic targets. Evidence points to a founder member of the matricial CCN family, NOV/CCN3, as a modulator of these inflammatory mediators. We thus investigated the possible involvement of NOV in a preclinical model of persistent inflammatory pain.MethodsWe used the complete Freund's adjuvant (CFA)-induced model of persistent inflammatory pain and cultured primary sensory neurons for in vitro experiments. The mRNA expression of NOV and pro-inflammatory factors were measured with real-time quantitative PCR, CCL2 protein expression was assessed using ELISA, MMP-2 and -9 activities using zymography. The effect of drugs on tactile allodynia was evaluated by the von Frey test.ResultsNOV was expressed in neurons of both dorsal root ganglia (DRG) and dorsal horn of the spinal cord (DHSC). After intraplantar CFA injection, NOV levels were transiently and persistently down-regulated in the DRG and DHSC, respectively, occurring at the maintenance phase of pain (15 days). NOV-reduced expression was restored after treatment of CFA rats with dexamethasone. In vitro, results based on cultured DRG neurons showed that siRNA-mediated inhibition of NOV enhanced IL-1β- and TNF-α-induced MMP-2, MMP-9 and CCL2 expression whereas NOV addition inhibited TNF-α-induced MMP-9 expression through β1 integrin engagement. In vivo, the intrathecal delivery of MMP-9 inhibitor attenuated mechanical allodynia of CFA rats. Importantly, intrathecal administration of NOV siRNA specifically led to an up-regulation of MMP-9 in the DRG and MMP-2 in the DHSC concomitant with increased mechanical allodynia. Finally, NOV intrathecal treatment specifically abolished the induction of MMP-9 in the DRG and, MMP-9 and MMP-2 in the DHSC of CFA rats. This inhibitory effect on MMP is associated with reduced mechanical allodynia.ConclusionsThis study identifies NOV as a new actor against inflammatory pain through regulation of MMPs thus uncovering NOV as an attractive candidate for therapeutic improvement in pain relief.
Highlights
Sustained neuroinflammation strongly contributes to the pathogenesis of pain
nephroblastoma overexpressed gene (NOV) is expressed by neurons of the dorsal root ganglion (DRG) and dorsal horn of the spinal cord (DHSC) NOV immunoreactivity (-IR) in nociceptive structures was first investigated by immunohistochemistry in the adult normal rat
Endogenous NOV knockdown upregulates matrix metalloproteinase (MMP)-2 and MMP-9 in vivo and increases mechanical allodynia of complete Freund’s adjuvant (CFA) rats We further investigated whether inhibition of NOV endogenous expression could modulate MMPs expression in vivo
Summary
Sustained neuroinflammation strongly contributes to the pathogenesis of pain. The clinical challenge of chronic pain relief led to the identification of molecules such as cytokines, chemokines and more recently matrix metalloproteinases (MMPs) as putative therapeutic targets. We have recently shown that in primary cultured astrocytes NOV expression is regulated by the cytokines TGF-b, TNF-a and IL-1b and that NOV induces the expression of cytokines (IL-10) and chemokines (CCL2 and CXCL1) through distinct integrins and signaling mechanisms [25,26] These findings suggest a potential role for NOV in neuroinflammatory processes and led us to investigate the involvement of NOV in the development and persistence of complete Freund’s adjuvant (CFA)-induced inflammatory pain. In this preclinical model of inflammatory pain, we show that NOV may have an important function in limiting the deleterious effects of pro-inflammatory cytokines on MMP-2 and MMP-9 expression in the nociceptive system, thereby exerting an anti-nociceptive effect
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