TY - JOUR
T1 - Lentiviral-mediated targeted NF-κB blockade in dorsal spinal cord glia attenuates sciatic nerve injury-induced neuropathic pain in the rat
AU - Meunier, Alice
AU - Latrémolière, Alban
AU - Dominguez, Elisa
AU - Mauborgne, Annie
AU - Philippe, Stéphanie
AU - Hamon, Michel
AU - Mallet, Jacques
AU - Benoliel, Jean Jacques
AU - Pohl, Michel
N1 - Funding Information:
We are grateful to François Cesselin, André Bogdan, Joao Braz and Chamsy Sarkis for critical reading of the manuscript and helpful discussions. We thank Justine Masson for her assistance with primary neuron-glia co-cultures. We thank Anning Lin and Hedi Mammeri for providing us with plasmids. This work was supported by grants from INSERM, Université Pierre et Marie Curie–Paris 6, Fondation pour la Recherche Médicale, Institut UPSA de la Douleur, and Institut pour la Recherche sur la Moelle épinière et l’Encéphale.
PY - 2007/4
Y1 - 2007/4
N2 - 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 κB (NF-κB) system is of particular interest, as numerous genes encoding inflammation- and pain-related molecules are controlled by this transcription factor. NF-κB 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-κB 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-κB super- repressor IκBα resulted in an inhibition of the NF-κB pathway activated in the rat spinal cord after sciatic nerve injury (chronic constriction injury, CCI). Concomitantly, IκBα 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-κB activity in spinal glia efficiently alleviates pain behavior in CCI rats, demonstrating the active participation of the glial NF-κB pathway in the development of neuropathic pain after peripheral nerve injury.
AB - 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 κB (NF-κB) system is of particular interest, as numerous genes encoding inflammation- and pain-related molecules are controlled by this transcription factor. NF-κB 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-κB 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-κB super- repressor IκBα resulted in an inhibition of the NF-κB pathway activated in the rat spinal cord after sciatic nerve injury (chronic constriction injury, CCI). Concomitantly, IκBα 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-κB activity in spinal glia efficiently alleviates pain behavior in CCI rats, demonstrating the active participation of the glial NF-κB pathway in the development of neuropathic pain after peripheral nerve injury.
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U2 - 10.1038/sj.mt.6300107
DO - 10.1038/sj.mt.6300107
M3 - Article
C2 - 17299402
AN - SCOPUS:33947227317
SN - 1525-0016
VL - 15
SP - 687
EP - 697
JO - Molecular Therapy
JF - Molecular Therapy
IS - 4
ER -