Painful mononeuropathy in C57BL/Wld mice with delayed wallerian degeneration: differential effects of cytokine production and nerve regeneration on thermal and mechanical hypersensitivity.

Wallerian degeneration with macrophage influx and production of proinflammatory cytokines is a critical factor in the development of hyperalgesia in animal models of neuropathic pain. We hypothesized that in the mouse strain with delayed Wallerian degeneration, the C57BL/Wld mouse, the temporal course of mechanical allodynia and thermal hyperalgesia as well as the temporal profile of cytokine expression after nerve injury would differ from normal mice. Here we used the model of chronic constriction injury of the sciatic nerve (CCI) to study the correlation of pain related behavior with peripheral nerve de- and regeneration and concomitant cytokine production. Indeed, after CCI, C57BL/Wld mice showed markedly reduced thermal hyperalgesia compared to normal C57BL/6 mice, temporally related to the delayed recruitment of hematogeneous macrophages to the injured nerve. Endoneurial tumor necrosis factor-alpha (TNF)-like immunoreactivity increased rapidly in normal mice but did so with a delayed time course in C57BL/Wld mice. In addition, the duration of mechanical allodynia was significantly prolonged in C57BL/Wld mice as compared to C57BL/6 mice, in accordance with the delay in regeneration of sensory nerve fibers in these mice. These results suggest that macrophage invasion and production of TNF may influence the development of thermal hyperalgesia and that regenerative activity is linked to mechanical allodynia in peripheral mononeuropathy.