Prooxidant-induced c-Src/nuclear factor kappa B-coupled signalling in sensory ganglia mediates cutaneous hyperalgesia

Persistent pain resulting from peripheral injury/inflammation is associated with altered sensitivity to cutaneous stimuli, which can manifest as hyperalgesia. The role of oxidant stress in the development, progression and maintenance of hyperalgesia is still not understood. Furthermore, there appears to be a relationship between c-Src kinase in the pain pathway and oxidative stress.

These results confirm that prooxidant-activated c-Src plays a role in initiating and maintaining hyperalgesia by regulating a stimulus-response coupling between the inflamed tissue and the DRG in the pain pathway. Our data also suggest that oxidant-induced dysregulation of c-Src/nuclear factor kappa B coupling may contribute to our understanding of the transition from acute to chronic dysfunctional pain state seen in many human diseases.

We have used a novel prooxidant inflammatory pain model that involves potassium peroxychromate (PPC), a unique prooxidant that produces the same reactants as activated phagocytes. This model was used to investigate the role of oxidant-activated c-Src in mediating hyperalgesia. We compared the effects of PP2 (a Src family kinase inhibitor) and c-Src siRNA on behavioural hyperalgesia with sodium stibogluconate (SSG) (a non-receptor tyrosine phosphatase inhibitor) and AG 1478 (a receptor tyrosine kinase inhibitor).

PP2 and c-Src siRNA attenuated PPC-induced thermal hyperalgesia, while SSG enhanced it. AG 1478 had no effect. PP2 decreased the levels of IL-1β, c-Src/inhibitory kappa B kinase complex formed and prostaglandin E2 produced in the dorsal root ganglia (DRG) ipsilateral to the inflamed paw, while SSG increased the levels of these parameters. c-Src siRNA decreased Src expression and activity in the DRG ipsilateral to the inflamed paw. Conclusions: These results confirm that prooxidant-activated c-Src plays a role in initiating and maintaining hyperalgesia by regulating a stimulus-response coupling between the inflamed tissue and the DRG in the pain pathway. Our data also suggest that oxidant-induced dysregulation of c-Src/nuclear factor kappa B coupling may contribute to our understanding of the transition from acute to chronic dysfunctional pain state seen in many human diseases.