REDUCED HYPERALGESIA IN NERVE-INJURED WLD MICE - RELATIONSHIP TO NERVE-FIBER PHAGOCYTOSIS, AXONAL DEGENERATION, AND REGENERATION IN NORMAL MICE

The pathogenesis of neuropathic pain states is influenced by inflammat ory factors associated with nerve injuries and may be mediated in part by the macrophage-dependent process of Wallerian degeneration, Macrop hages play a dominant role in the Wallerian (axonal) degeneration that characterizes the painful chronic constriction injury model of neurop athy by liberating proinflammatory cytokines at the site of nerve inju ry, These cytokines directly affect the structural integrity of neural systems and have been implicated in the development of hyperalgesic s tates, We hypothesized that interference with the pathologic process o f Wallerian degeneration would alter the development of the neuropathi c pain state, To test this hypothesis, we studied the development of t hermal hyperalgesia in the chromic constriction injury model of neurop athy using normal mice and mice of the WLD strain in which recruitment of macrophages to the site of nerve injury and Wallerian degeneration are delayed, We compared the onset and magnitude of the hyperalgesia with quantitative measures of nerve injury including the phagocytic ce llular activity associated with Wallerian degeneration. In C57BL/6J (6 J) mice, hyperalgesia peaked 3-10 days after placement of the ligature s, qualitatively matching the response previously reported for rats, I n C57BL/WLD (WLD) mice, there was reduced hyperalgesia temporally asso ciated with reduced numbers of phagocytic cells in the injured nerve, In injured WLD nerves there was a reduced rate of axonal degeneration compared to similarly injured 6J nerves, Regeneration was correspondin gly delayed in the WLD animals, The results suggest that the process o f Wallerian degeneration is a key factor in the pathogenesis of hypera lgesia, Continued development of mouse models of neuropathic pain nili be important in exploring the molecular basis of neuropathic pain, In terference with the cellular mediators of Wallerian degeneration may b e a useful therapeutic strategy that might modulate the onset and magn itude of hyperalgesia following nerve injury. (C) 1996 Academic Press, Inc.