Altered pain behavior and regeneration after nerve injury in TNF receptor deficient mice.

The pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha is an important mediator in hyperalgesia, nerve injury, and regeneration. Here, we used mice deficient of TNF receptor (TNFR) 1 or 2 to investigate the role of TNF signaling via receptor in each pain behavior and nerve de- and regeneration after chronic constriction injury (CCI) of the sciatic nerve. We found an absence of thermal hyperalgesia in mice deficient of TNFR1 and a reduction in mechanical and cold allodynia in mice deficient of TNFR1 or TNFR2 compared with wild-type mice. Nerve conduction studies and nerve pathology did not reveal major differences between genotypes in the temporal course of de- and regeneration of the nerve. We propose that the functional effects of the TNFRs on pain symptoms are independent of effects on nerve regeneration. Furthermore, the differential action of TNF via each of its receptors should be taken into account when considering clinical trials with TNF inhibitors for pain.