Anterograde transport of tumor necrosis factor-α in the intact and injured rat sciatic nerve

Tumor necrosis factor-alpha (TNF) appears as a key player at both central and peripheral terminals in early degenerative pathology and pain behavior after peripheral nerve injury. Recent studies suggest that TNF may be axonally transported and thereby contribute to these central and peripheral actions. To characterize this transport, we used a double ligation (DL) procedure that distinguishes between anterograde and retrograde flow to visualize the axonal transport of endogenous TNF compared with the neurotrophin nerve growth factor (NGF) and to the neuropeptide calcitonin gene-related peptide (CGRP). In the intact nerve, TNF and CGRP immunoreactivity predominantly accumulated proximal to the DL (anterograde transport), whereas NGF displayed exclusive retrograde transport. At 20 hr after chronic constrictive injury (CCl), the anterograde transport of TNF and CGRP to the nerve injury site was dramatically increased. The results were corroborated by the analysis of axonal transport of exogenously applied I-125-TNF and I-125-NGF. After intraneural injection, I-125-TNF accumulated proximally to a DL, suggesting anterograde transport. In the unligated nerve, I-125-TNF was specifically transported anterogradely to the innervated muscle but not to skin. After CCl, I-125-TNF accumulated proximally to the peripheral nerve injury site, and endogenous TNF was exclusively increased in medium-sized and large dorsal root ganglion (DRG) neurons, suggesting that DRG neurons are a major contributing source of increased TNF traffic in the injured sciatic nerve. Our results suggest that anterograde transport of TNF plays a major role in the early neuronal response to peripheral nerve injury at sites distal to the cell body.