Lentiviral-mediated Targeted NF-κB Blockade in Dorsal Spinal Cord Glia Attenuates Sciatic Nerve Injury–induced Neuropathic Pain in the Rat

Abstract

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.

SOCS3-Mediated Blockade of JAK/STAT3 Signaling Pathway Reveals Its Major Contribution to Spinal Cord Neuroinflammation and Mechanical Allodynia after Peripheral Nerve Injury

“…Consistent with our previous data (Meunier et al, 2007(Meunier et al, , 2008, vector delivery into the spinal cord of rats did not modify their basal pain sensitivity (data not shown). Similarly, the mechanical pain sensitivity of sciatic nerve sham-operated rats assessed with von Frey filaments did not significantly differ from that of naive animals at any time point studied (data not shown).…”

“…Here, we selectively inhibited JAK/STAT3 function in vivo in rat spinal cord glia by enhancing the local production of SOCS3 using gliotropic lentiviral vectors (LVs) (Meunier et al, 2007(Meunier et al, , 2008. We assessed the effects of SOCS3 on JAK/STAT3 signaling and explored the consequences of this selective local blockade of JAK/STAT3 on downstream signaling responses and pain hypersensitivity in a preclinical model of neuropathic pain induced by chronic constriction injury of the sciatic nerve (CCI) in rats (Bennett and Xie, 1988).…”

Lentiviral vectors for gene transfer into the spinal cord glial cells

“…This local inhibition of NF-kB activity in glial cells of the (unilateral) lumbar spinal cord attenuated the thermal hyperalgesia and mechanical allodynia that develop after CCI of the sciatic nerve. 45 Our data thus demonstrate that VSV-pseudotyped HIV-derived vectors can mediate local gene transfer Figure 2 In vivo, lentiviral enhanced green fluorescent protein (LV-EGFP) transduces preferentially astrocytes and microglial cells in the dorsal horn of the rat spinal cord. A majority of EGFP fluorescent cells (in green) were colabeled with glial fibrillary acidic protein (GFAP) (astrocytic marker, a) or with OX42 (microglial marker, b).…”

NF-κB deficit in spinal motoneurons in patients with sporadic amyotrophic lateral sclerosis – a pilot study

“…This could be due to detrimental action of excessive amounts of pro-inflammatory cytokines, excitotoxins and free radicals produced and released by the glial cells [6,16,27]. Some studies in a rat model of traumatic CNS injury have shown that blockade of the NF-κB-mediated signaling pathway in astrocytes can exert a neuroprotective effect [30]. However, an attempt to use the same strategy for motoneuron protection in a mouse model of ALS has failed.…”