Lentiviral-mediated targeted NF-kappaB blockade in dorsal spinal cord glia attenuates sciatic nerve injury-induced neuropathic pain in the rat.
Neuropathic pain developing after peripheral nerve injury is associated with altered neuronal and glial cell functions in the spinal cord. Activated glia produces algogenic mediators, exacerbating pain. Among the different intracellular pathways possibly involved in the modified glial function, the nuclear factor kappaB (NF-kappaB) system is of particular interest, as numerous genes encoding inflammation- and pain-related molecules are controlled by this transcription factor. NF-kappaB is a pleiotropic factor also involved in central nervous system homeostasy. To study its role in chronic pain, it is thus essential to inhibit the NF-kappaB pathway selectively in activated spinal glial cells. Here, we show that when restricted to spinal cord and targeted to glial cells, lentiviral vector-mediated delivery of NF-kappaB super- repressor IkappaBalpha resulted in an inhibition of the NF-kappaB pathway activated in the rat spinal cord after sciatic nerve injury (chronic constriction injury, CCI). Concomitantly, IkappaBalpha overproduction prevented the enhanced expression of interleukin-6 and of inducible nitric oxide synthase associated with chronic constriction injury and resulted in prolonged antihyperalgesic and antiallodynic effects. These data show that targeted blockade of NF-kappaB activity in spinal glia efficiently alleviates pain behavior in CCI rats, demonstrating the active participation of the glial NF-kappaB pathway in the development of neuropathic pain after peripheral nerve injury.
Meunier
Alice
A
INSERM, UMR S 713, Paris, France.
Latrémolière
Alban
A
Dominguez
Elisa
E
Mauborgne
Annie
A
Philippe
Stéphanie
S
Hamon
Michel
M
Mallet
Jacques
J
Benoliel
Jean-Jacques
JJ
Pohl
Michel
M
D000818:Animals; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006930:Hyperalgesia / Q000628:therapy; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics; D016086:Lentivirus / Q000235:genetics*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D009437:Neuralgia / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D009457:Neuroglia / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D051381:Rats; D012584:Sciatic Nerve / Q000293:injuries* / Q000503:physiopathology; D013116:Spinal Cord / Q000503:physiopathology*
D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat