Involvement of spinal cord nuclear factor kappaB activation in rat models of proinflammatory cytokine-mediated pain facilitation.
Proinflammatory cytokines, such as interleukin-1beta 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 kappaB (NF-kappaB). In turn, NF-kappaB 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-kappaB is involved in gp120-induced pain behaviour in Sprague-Dawley rats. Intrathecal administration of NF-kappaB 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-kappaB within the spinal cord. To reveal NF-kappaB activation, we assessed inhibitory factor kappaBalpha (IkappaBalpha) mRNA expression by in situ hybridization, as NF-kappaB activation up-regulates IkappaBalpha gene expression as part of an autoregulatory feedback loop. No or low levels of IkappaBalpha mRNA were detected in the lumbar spinal cord of vehicle-injected rats, whereas IkappaBalpha mRNA expression was markedly induced in the spinal cord following intrathecal gp120 in predominantly astrocytes and endothelial cells. Moreover, IkappaBalpha mRNA expression positively correlated with proinflammatory cytokine protein levels in lumbosacral cerebrospinal fluid. Together, these results demonstrate that spinal cord NF-kappaB activation is involved, at least in part, in exaggerated pain states.
Ledeboer
Annemarie
A
Department of Psychology & Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA. ledeboer@psych.colorado.edu
Gamanos
Michael
M
Lai
Wenmin
W
Martin
David
D
Maier
Steven F
SF
Watkins
Linda R
LR
Quan
Ning
N
D000818:Animals; D000975:Antioxidants; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D016207:Cytokines / Q000134:cerebrospinal fluid*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D008840:Microfilament Proteins; D016328:NF-kappa B / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D010455:Peptides / Q000008:administration & dosage; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism*; D013859:Thiocarbamates / Q000008:administration & dosage; D013997:Time Factors
C100745:Aif1 protein, rat; D000975:Antioxidants; D002135:Calcium-Binding Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D015699:HIV Envelope Protein gp120; D008840:Microfilament Proteins; D016328:NF-kappa B; D010455:Peptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C118258:SN50 peptide; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D011392:Proline