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

Proinflammatory cytokines, such as interleukin-1 beta and tumour necrosis factor-alpha, 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 kappa B (NF-kappa B). In turn, NF-kappa B 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-kappa B is involved in gp120-induced pain behaviour in Sprague-Dawley rats. Intrathecal administration of NF-kappa B 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-kappa B within the spinal cord. To reveal NF-kappa B activation, we assessed inhibitory factor kappa B alpha (I kappa B alpha) mRNA expression by in situ hybridization, as NF-kappa B activation up-regulates I kappa B alpha gene expression as part of an autoregulatory feedback loop. No or low levels of I kappa B alpha mRNA were detected in the lumbar spinal cord of vehicle-injected rats, whereas I kappa B alpha mRNA expression was markedly induced in the spinal cord following intrathecal gp120 in predominantly astrocytes and endothelial cells. Moreover, I kappa B alpha mRNA expression positively correlated with proinflammatory cytokine protein levels in lumbosacral cerebrospinal fluid. Together, these results demonstrate that spinal cord NF-kappa B activation is involved, at least in part, in exaggerated pain states.