Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat

Abstract

Neuropathic pain accompanies peripheral nerve injury following a variety of insults including metabolic disorders, traumatic injury, and exposure to neurotoxins such as vincristine and taxol. Vincristine, a microtubule depolymerizing drug, produces a peripheral neuropathy in humans that is accompanied by painful paresthesias and dysesthesias (Sandler et al., [1969] Neurology 19:367-374; Holland et al. [1973] Cancer Res. 33:1258-1264). The recent development of an animal model of vincristine-induced neuropathy provides an opportunity to investigate mechanisms underlying this form of neuropathic pain. Systemic vincristine (100 microg/kg) produces hyperalgesia to mechanical stimuli during the second week of administration, which persists for more than a week (Aley et al. [1996] Neuroscience 73:259-265). To test the hypothesis that changes in microtubule structure in nociceptive sensory neurons accompany vincristine-induced hyperalgesia, we analyzed unmyelinated axons in saphenous nerves of vincristine-treated rats. This study constitutes the 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 the 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 significant increase in the cross-sectional area of unmyelinated axons, suggesting swelling of axons. In addition, vincristine-treated axons had significantly fewer microtubules cut in cross-section and significantly more tangentially oriented microtubules per axon compared to controls. These results suggest that vincristine causes disorganization of the axonal microtubule cytoskeleton, as well as an increase in the caliber of unmyelinated sensory axons.

Paclitaxel- and vincristine-evoked painful peripheral neuropathies: Loss of epidermal innervation and activation of Langerhans cells

“…In contrast, relatively low systemic doses of paclitaxel and vincristine produce signs of pain hypersensitivity, including allodynia and hyper-algesia (Aley et al, 1996;Authier et al, 1999Authier et al, , 2000Authier et al, , 2003Polomano et al, 2001;Nozaki-Taguchi et al, 2001;Siau and Bennett, 2006). Light-and electron microscopic studies of peripheral nerves from rats with low-dose paclitaxel-and vincristine-evoked painful peripheral neuropathies have failed to find any axonal degeneration in peripheral nerve (Tanner et al, 1998a;Polomano et al, 2001;Topp et al, 2000;. Thus, the cause of paclitaxel-and vincristine-evoked painful neuropathies is unknown, and the relation between the neuropathic pain state and the neuropathy per se is unclear.…”

“…Previous examinations of peripheral nerve axons from rats with paclitaxel-and vincristine-evoked painful peripheral neuropathies have found small increases in the average diameter of C fibers and in the incidence of microtubules with an atypical orientation in A and C fibers (Tanner et al, 1998a;Topp et al, 2000;. The functional consequences of these changes are unclear.…”

Regulation of Piezo2 Mechanotransduction by Static Plasma Membrane Tension in Primary Afferent Neurons

“…Unless under extreme conditions, such as exposure of wounded skin and ulcerated oral mucosa tissues directly to water, the osmotic environment surrounding primary afferents is unlikely to be disturbed to the degree similar to our experimental condition. Interestingly, two previous studies show primary afferent axon swelling to result in 18 -21% increases in the axonal cross-sectional area in vincristine-induced neuropathy in rats (34,35). It will be interesting to study in the future whether Piezo2-mediated mechanotransduction may be sensitized under these conditions.…”

Animal Models of Chemotherapy-Evoked Painful Peripheral Neuropathies

“…The most used model is that developed by Aley et al, 9 and its adaptation by Weng et al 10 They described a mechanical allodynia/hyperalgesia and a heat hyperalgesia. To investigate physiopathology of this model, Tanner et al 11,12 reported abnormal microtubule assemblies and axonal swelling in myelinated and unmyelinated fibers, and described that vincristine caused half the C-fiber nociceptors to become markedly hyper-responsive to mechanical stimulation. 13 Studying the role of transient receptor potential vaniloid 4, Alessandri et al…”