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. 2017 Sep;158(9):1647-1655.
doi: 10.1097/j.pain.0000000000000953.

Early life vincristine exposure evokes mechanical pain hypersensitivity in the developing rat

Katie A Schappacher  1   2 , Lauren Styczynski  1 , Mark L Baccei  1
Affiliations

Early life vincristine exposure evokes mechanical pain hypersensitivity in the developing rat

Katie A Schappacher et al. Pain. 2017 Sep.

Abstract

Vincristine (VNC) is commonly used to treat pediatric cancers, including the most prevalent childhood malignancy, acute lymphoblastic leukemia. Although clinical evidence suggests that VNC causes peripheral neuropathy in children, the degree to which pediatric chemotherapeutic regimens influence pain sensitivity throughout life remains unclear, in part because of the lack of an established animal model of chemotherapy-induced neuropathic pain during early life. Therefore, this study investigated the effects of VNC exposure between postnatal days (P) 11 and 21 on mechanical and thermal pain sensitivity in the developing rat. Low doses of VNC (15 or 30 μg/kg) failed to alter nociceptive withdrawal reflexes at any age examined compared with vehicle-injected littermate controls. Meanwhile, high dose VNC (60 μg/kg) evoked mechanical hypersensitivity in both sexes beginning at P26 that persisted until adulthood and included both static and dynamic mechanical allodynia. Hind paw withdrawal latencies to noxious heat and cold were unaffected by high doses of VNC, suggesting a selective effect of neonatal VNC on mechanical pain sensitivity. Gross and fine motor function appeared normal after VNC treatment, although a small decrease in weight gain was observed. The VNC regimen also produced a significant decrease in intraepidermal nerve fiber density in the hind paw skin by P33. Overall, the present results demonstrate that high-dose administration of VNC during the early postnatal period selectively evokes a mechanical hypersensitivity that is slow to emerge during adolescence, providing further evidence that aberrant sensory input during early life can have prolonged consequences for pain processing.

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Conflict of interest statement

The authors declare that they have no conflicts of interest with any of the work presented in this manuscript.

Figures

Figure 1
Figure 1. Vincristine (VNC) treatment significantly reduces weight gain in both sexes. (A)
In male rats treated with VNC, there is a significant reduction in weight gain starting at P21 which persisted until the end of testing (F(8,433) = 11.03, p < 0.0001, n = 18 – 27, 2-way ANOVA). (B) In females, VNC significantly attenuates weight gain starting at P19 (F(8,451) = 7.40, p < 0.0001, n = 14 – 27, 2-way ANOVA; *p < 0.05; ***p < 0.001; ****p < 0.0001; Holm-Sidak post hoc analysis). Each rat received one intraperitoneal injection (arrow) on P11, 13, 17, 19, and 21.
Figure 2
Figure 2. Neonatal vincristine administration does not impact gross or fine motor function in the developing rat. (A)
VNC treatment does not significantly affect gross motor function compared to vehicle-treated littermate controls on the rotarod test (F(1,192) = 0.18, p = 0.82, n = 17, 2-way ANOVA). (B) Assessment of fine motor function demonstrated no difference in performance on the foot fault test between vehicle and VNC treated animals (F(1,76) = 0.08, p = 0.78, n = 10 – 16 in each group, 2-way ANOVA).
Figure 3
Figure 3. Neonatal VNC exposure results in static mechanical allodynia by P26 in both sexes
VNC treatment produces a delayed reduction in mechanical withdrawal thresholds in response to von Frey hair (VFH) application in both (A) male and (B) female rats compared to vehicle controls. Male VFH: (F(10,493) = 3.42, p = 0.0002, n = 18 – 27 in each group); Female VFH: (F(10,457) = 6.35, p < 0.0001, n = 14 – 27, 2-way ANOVA; *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001; Holm-Sidak post hoc analysis). Each rat received one intraperitoneal injection (arrow) on P11, 13, 17, 19, and 21.
Figure 4
Figure 4. Early life VNC produces dynamic mechanical allodynia and static mechanical hyperalgesia. (A)
Plot of allodynia score of hindpaw withdrawal in response to a paintbrush stimulus as a function of postnatal age following neonatal VNC treatment. A significant main effect of VNC treatment was observed when compared to vehicle-treated littermate controls (F(1,134) = 8.32, p = 0.0046, n = 19 – 26 in each group, 2-way ANOVA; **p < 0.01; Holm-Sidak post hoc analysis), suggesting the presence of dynamic mechanical allodynia after VNC. (B) Plot of frequency of hindpaw withdrawal in response to a pinprick stimulus at different ages after early VNC exposure. A significant main effect of VNC treatment was observed when compared to vehicle-treated littermate controls (F(1,97) = 12.00, p = 0.0008, n = 13 – 23, 2-way ANOVA; ***p < 0.001; Holm-Sidak post hoc analysis).
Figure 5
Figure 5. VNC during the early postnatal period does not significantly affect withdrawal thresholds to noxious heat or cold. (A)
VNC did not significantly impact withdrawal latencies to noxious heat (F(1,145) = 0.06, p = 0.81, n = 16, 2-way ANOVA). (B) VNC also failed to alter withdrawal latencies to noxious cold stimuli (F(1,238) = 0.01, p = 0.92, n = 25, 2-way ANOVA).
Figure 6
Figure 6. Neonatal VNC treatment leads to decreased epidermal innervation and the presence of PGP9.5-positive Langerhans cells at P33
Confocal images of representative plantar skin sections immunostained for PGP9.5 (green) and collagen IV (red) from vehicle and VNC treated animals. On P33, VNC treated animals (B) had fewer PGP9.5-stained intraepidermal nerve fibers compared to those treated with saline (A). Arrows point to faintly stained Langerhans cells. Scale bar = 50 μm. (C) VNC leads to a reduction in PGP9.5-immunoreactive intraepidermal nerve fibers (IENF) two weeks after the end of treatment (F(1,56) = 5.616, p = 0.021, 2-way ANOVA, *p < 0.05; Holm-Sidak post hoc analysis). (D) VNC leads to an increased presence of PGP9.5-positive Langerhans cells at P33 (*p = 0.017, unpaired t-test).
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