Abstract
Herniation of the intervertebral disc may be associated with a painful neuropathy (sciatica) or motor weakness that is partly mediated by inflammatory cell infiltration and proinflammatory cytokine expression. Much of the cytokine-mediated signaling and inflammatory events falls downstream of activation of the transcription factor, NF- κB. We have previously demonstrated an ability to visualize NF- κB activity in a transgenic NF-κB luciferase reporter mouse, following induction of arthritis in the knee joint.1 The temporal and spatial pattern of NF-κB-luc correlated with development of painful sensitivities in the arthritis model suggesting an ability to use in vivo imaging to rapidly screen progression of pathology and therapeutic interventions.
Here, we investigate the temporal and spatial development of NF-κB activity in the NF-κB-luc reporter mouse following induction of peripheral nerve injury (sciatic nerve constriction) and test for relationships amongst pain-related sensitivities, serum levels of NF-κB-related cytokines, and regional measures of NF-κB activity. Our work in this model system revealed that NF-κB B activity following nerve injury is elevated in the region of the affected nerve, with luciferase production specifically from the sciatic nerve and the surrounding musculature. Temporal elevations in NF-κB activity were noted beginning at 3 days after surgery, and correlated with mechanical (von Frey testing, Spearman ρ-0.84) and thermal (hyperalgesia at paw, Spearman ρ -0.80) sensitivity in a distinctly nonlinear fashion. NF- κB activity also correlated with serum interleukin 6 levels (Spearman ρ 0.75), but not with other measured cytokines. Delivery of the NF- κB specific inhibitor, NEMO-binding domain peptide NBD, was able to reduce NF- κB-luc signal, restore thermal sensitivity to sham levels, and restore mechanical sensitivity to near sham levels. These findings are important for demonstrating a direct link between the NF- κB-luc signal and pain-related measures. Together this work suggests that longitudinal and spatially resolved in vivo imaging can be useful to characterize cytokine-related sensitivities in neuropathy, with implications for radiculopathy associated with intervertebral disc herniation.
None declared
Bowles RD, Mata BA, Bell RD, et al. In vivo luminescent imaging of NF-κB activity and serum cytokine levels predict pain sensitivities in a rodent model of osteoarthritis. Arthritis Rheum 2013; November 18 (Epub ahead of print); doi: 10.1002/art.38279
(Left) Luciferase signaling originating from constricted sciatic nerve in NF-κB-luc transgenic mouse model. (Right) Quantitation of luciferase in region of interest corresponding to sciatic nerve.