MICROTUBULE DISORIENTATION AND AXONAL SWELLING IN UNMYELINATED SENSORY AXONS DURING VINCRISTINE-INDUCED PAINFUL NEUROPATHY IN RAT

Neuropathic pain accompanies peripheral nerve injury following a varie ty of insults including metabolic disorders, traumatic injury, and exp osure to neurotoxins such as vincristine and taxol. Vincristine, a mic rotubule depolymerizing drug, produces a peripheral neuropathy in huma ns that is accompanied by painful paresthesias and dysesthesias (Sandl er et al., [1969] Neurology 19:367-374; Holland et al. [1973] Cancer R es. 33:1258-1264). The recent development of an animal model of vincri stine-induced neuropathy provides an opportunity to investigate mechan isms underlying this form of neuropathic pain. Systemic vincristine (1 00 mu g/kg) produces hyperalgesia to mechanical stimuli during the sec ond week of administration, which persists for more than a week (Aley et al. [1996] Neuroscience 73:259-265). To test the hypothesis that ch anges in microtubule structure in nociceptive sensory neurons accompan y vincristine-induced hyperalgesia, we analyzed unmyelinated axons in saphenous nerves of vincristine-treated rats. This study constitutes t he first quantitative ultrastructural analysis of the cytoskeleton of unmyelinated axons in peripheral nerve during neuropathic hyperalgesia . There was no evidence of unmyelinated fiber loss or a decrease in th e number of microtubules per axons. There was, however, a significant decrease in microtubule density in unmyelinated axons from vincristine -treated rats. This decrease in microtubule density was due to a signi ficant increase in the cross-sectional area of unmyelinated axons, sug gesting swelling of axons. In addition, vincristine-treated axons had significantly fewer microtubules cut in cross-section and significantl y more tangentially oriented microtubules per axon compared to control s. These results suggest that vincristine causes disorganization of th e axonal microtubule cytoskeleton, as well as an increase in the calib er of unmyelinated sensory axons. (C) 1998 Wiley-Liss, Inc.