WALLERIAN DEGENERATION IS REQUIRED FOR BOTH NEUROPATHIC PAIN AND SYMPATHETIC SPROUTING INTO THE DRG

Chronic loose constriction of the sciatic nerve produces mechanoallody nia and thermal hyperalgesia in rats and mice, and the behaviour devel ops 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 pai n, yet the site at which this sympathetic-sensory coupling remains unk nown. It has been shown that following sciatic nerve transection or sp inal nerve lesion, sympathetic axons invade the dorsal root ganglion ( DRG) where they sometimes form pericellular baskets around mostly larg e diameter DRG neurons - a possible anatomical substrate for sympathet ically maintained pain (SMP). The signal for the sympathetic invasion of the DRG has nor yet been shown, but associated with Wallerian degen eration is the upregulation of nerve growth factor (NGF) in the distal stump of the partially injured nerve, which may be retrograde-transpo rted to the DRG in uninjured sensory axons to induce sprouting of symp athetic axons. To investigate the role of Wallerian degeneration in th e development of neuropathic pain and sympathetic sprouting in the DRG , we have made use of a strain of mouse (C57Bl/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 s ciatic nerve with 3 ligatures, and allowed these mice to survive for a further 1, 2 or 3 weeks, during which time we assessed mechanoallodyn ia and thermal hyperalgesia. At the end of the testing period, the lum bar DRGs were removed for glyoxylic acid-induced fluorescence of catec holamines to determine the extent to which sympathetic axons had invad ed the DRG. We found that both indices of neuropathic pain were signif icantly attenuated in Wld mice compared to wild-type mice, with the wi ld-type mice increasing in sensitivity to both thermal and mechanical stimulation in the first week post-operative (PO), while Wld mice show ed marked hypoalgesia following CCI. Histological examination of the D RG showed that sympathetic sprouting into the DRG was also markedly de layed 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 incr eased at 3 weeks PO. These results show that Wallerian degeneration is tightly linked to the development of both pain and sympathetic sprout ing following CCI, and we speculate on the possible role of NGF as a m ediator of both phenomena. (C) 1997 International Association for the Study of Pain. Published by Elsevier Science B.V.