Involvement of spinal cord nuclear factor κB activation in rat models of proinflammatory cytokine‐mediated pain facilitation

Abstract

Proinflammatory cytokines, such as interleukin‐1β and tumour necrosis factor‐α, are released by activated glial cells in the spinal cord and play a major role in pain facilitation. These cytokines exert their actions, at least partially, through the activation of the transcription factor, nuclear factor κB (NF‐κB). In turn, NF‐κB regulates the transcription of many inflammatory mediators, including cytokines. We have previously shown that intrathecal injection of the human immunodeficiency virus‐1 (HIV‐1) envelope glycoprotein, gp120, induces mechanical allodynia via the release of proinflammatory cytokines. Here, we investigated whether NF‐κB is involved in gp120‐induced pain behaviour in Sprague–Dawley rats. Intrathecal administration of NF‐κB inhibitors, pyrrolidinedithiocarbamate (PDTC) and SN50, prior to gp120 partially attenuated gp120‐induced allodynia. In addition, PDTC delayed and reversed allodynia in a model of neuropathic pain induced by sciatic nerve inflammation. These observations suggest that intrathecal gp120 may lead to activation of NF‐κB within the spinal cord. To reveal NF‐κB activation, we assessed inhibitory factor κBα (IκBα) mRNA expression by in situ hybridization, as NF‐κB activation up‐regulates IκBα gene expression as part of an autoregulatory feedback loop. No or low levels of IκBα mRNA were detected in the lumbar spinal cord of vehicle‐injected rats, whereas IκBα mRNA expression was markedly induced in the spinal cord following intrathecal gp120 in predominantly astrocytes and endothelial cells. Moreover, IκBα mRNA expression positively correlated with proinflammatory cytokine protein levels in lumbosacral cerebrospinal fluid. Together, these results demonstrate that spinal cord NF‐κB activation is involved, at least in part, in exaggerated pain states.