Effects of Neutralizing Antibodies to Tnf‐alpha on Pain‐related Behavior and Nerve Regeneration in Mice With Chronic Constriction Injury

Abstract

Inhibition of proinflammatory cytokines reduces hyperalgesia in animal models of painful neuropathy. We set out to investigate the consequences of this treatment for nerve regeneration. Here we examined the sequels of epineurial application of neutralizing antibodies to tumor necrosis factor‐alpha (TNF) in chronic constriction injury (CCI) of the sciatic nerve in C57/BL 6 mice. The mice were tested behaviorally for manifestations of thermal hyperalgesia and mechanical allodynia. Nerve regeneration was assessed by morphometry of myelinated nerve fibers in the sciatic nerve and of the epidermal innervation density in the glabrous skin of the hindpaws. Antibodies to TNF reduced thermal hyperalgesia and mechanical allodynia after CCI. Myelinated fiber density in the sciatic nerve was reduced to 30% of normal on day 7 after surgery, and reached 60% on day 45, with no difference between antibody‐treated and untreated animals. Epidermal innervation density as shown by PGP 9.5 and CGRP immunohistochemistry was reduced to 25–47% at both time points after CCI, again without differences between antibody treated and untreated mice. Myelinated fiber density but not epidermal innervation density was correlated to thermal and mechanical withdrawal thresholds. We conclude that neutralization of endoneurial TNF attenuates pain related behavior but has no effect on nerve regeneration. Furthermore, the number of epidermal nerve fibers is not relevant to the magnitude of behavioral hyperalgesia in CCI.

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“…Levels of TNF- α, IL-6, and IL-1β are all increased following peripheral nerve injury and are temporally aligned with the onset and maintenance of hyperalgesia and/or allodynia (reviewed in Marchand et al, 2005 ). Furthermore, administration of IL-6, IL-1β, and TNF- α antagonists can reduce the magnitude of allodynia, hyperalgesia, and pain behaviors following nerve damage ( Sommer et al, 2001a ; Sommer et al, 2001b ; Lindenlaub et al, 2000 ; Schafers et al, 2001 ; Sommer et al, 1999 ). Similarly, IL-6 knockout mice demonstrate less hyperalgesia following nerve damage than their wildtype littermates ( Ramer et al, 1998 ; Murphy et al, 1999 ).…”