Wallerian degeneration is required for both neuropathic pain and sympathetic sprouting into the DRG

Abstract

Chronic loose constriction of the sciatic nerve produces mechanoallodynia and thermal hyperalgesia in rats and mice, and the behaviour develops during the time in which the nerve distal to the ligature site is undergoing Wallerian degeneration. There is a sympathetic component to the pain generated by this and other rodent models of neuropathic pain, yet the site at which this sympathetic-sensory coupling remains unknown. It has been shown that following sciatic nerve transection or spinal nerve lesion, sympathetic axons invade the dorsal root ganglion (DRG) where they sometimes form pericellular baskets around mostly large diameter DRG neurons--a possible anatomical substrate for sympathetically maintained pain (SMP). The signal for the sympathetic invasion of the DRG has not yet been shown, but associated with Wallerian degeneration is the upregulation of nerve growth factor (NGF) in the distal stump of the partially injured nerve, which may be retrograde-transported to the DRG in uninjured sensory axons to induce sprouting of sympathetic axons. To investigate the role of Wallerian degeneration in the development of neuropathic pain and sympathetic sprouting in the DRG, we have made use of a strain of mouse (C57B1/Wld) in which Wallerian degeneration following nerve injury is delayed. We gave wild-type or Wld mice chronic constriction injuries (CCI) by loosely ligating the sciatic nerve with 3 ligatures, and allowed these mice to survive for a further 1, 2 or 3 weeks, during which time we assessed mechanoallodynia and thermal hyperalgesia. At the end of the testing period, the lumbar DRGs were removed for glyoxylic acid-induced fluorescence of catecholamines to determine the extent to which sympathetic axons had invaded the DRG. We found that both indices of neuropathic pain were significantly attenuated in Wld mice compared to wild-type mice, with the wild-type mice increasing in sensitivity to both thermal and mechanical stimulation in the first week post-operative (PO), while Wld mice showed marked hypoalgesia following CCI. Histological examination of the DRG showed that sympathetic sprouting into the DRG was also markedly delayed in Wld mice compared to wild-type mice: 1 week following injury, sympathetic fibres had invaded the ipsilateral DRG of wild-type mice, while sprouting in ipsilateral DRG of Wld mice was only slightly increased at 3 weeks PO. These results show that Wallerian degeneration is tightly linked to the development of both pain and sympathetic sprouting following CCI, and we speculate on the possible role of NGF as a mediator of both phenomena.