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 inflammatory factors associated with nerve injuries and may be mediated in part by the macrophage-dependent process of Wallerian degeneration. Macrophages play a dominant role in the Wallerian (axonal) degeneration that characterizes the painful chronic constriction injury model of neuropathy by liberating proinflammatory cytokines at the site of nerve injury. These cytokines directly affect the structural integrity of neural systems and have been implicated in the development of hyperalgesic states. We hypothesized that interference with the pathologic process of Wallerian degeneration would alter the development of the neuropathic pain state. To test this hypothesis, we studied the development of thermal hyperalgesia in the chronic constriction injury model of neuropathy 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 cellular activity associated with Wallerian degeneration. In C57BL/6J (6J) mice, hyperalgesia peaked 3-10 days after placement of the ligatures, qualitatively matching the response previously reported for rats. In C57BL/WLD (WLD) mice, there was reduced hyperalgesia temporally associated 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 correspondingly delayed in the WLD animals. The results suggest that the process of Wallerian degeneration is a key factor in the pathogenesis of hyperalgesia. Continued development of mouse models of neuropathic pain will be important in exploring the molecular basis of neuropathic pain. Interference with the cellular mediators of Wallerian degeneration may be a useful therapeutic strategy that might modulate the onset and magnitude of hyperalgesia following nerve injury.
Myers
R R
RR
Department of Veterans Affairs, San Diego, La Jolla, California, USA.
Heckman
H M
HM
Rodriguez
M
M
D000818:Animals; D001369:Axons / Q000502:physiology; D004487:Edema / Q000473:pathology; D005260:Female; D006930:Hyperalgesia / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009412:Nerve Fibers / Q000502:physiology; D009416:Nerve Regeneration; D009422:Nervous System Diseases / Q000473:pathology; D010587:Phagocytosis; D012584:Sciatic Nerve / Q000293:injuries* / Q000473:pathology; D014855:Wallerian Degeneration; D014949:Wounds, Nonpenetrating / Q000473:pathology / Q000503:physiopathology*