Peptidergic intraepidermal nerve fibers in the skin contribute to the neuropathic pain in paclitaxel-induced peripheral neuropathy

Paclitaxel in chemotherapy-induced peripheral neuropathy (CIPN) is predominantly with a dose-limiting effect on neuropathic pain in clinical strategy. In the present study, the relationship between the neuropathic pain and nerve degeneration in paclitaxel CIPN was investigated. Adult male Sprague–Dawley (SD) rats were divided into three paclitaxel groups (0.5, 1.0, 2.0 mg/kg) and a vehicle group with four intraperitoneal (i.p.) injections on alternating days. Our results demonstrated that the paclitaxel groups significantly exhibited the reductions of thermal hyperalgesia and mechanical allodynia. The neurotoxicity of paclitaxel conveyed the degeneration of intraepidermal nerve fibers (IENFs) in hindpaw glabrous skin. Nevertheless, the influence of paclitaxel to the peptidergic IENFs are even unknown. The skin innervation of protein gene product 9.5 (PGP 9.5)-immunoreactive (IR) IENFs in paclitaxel groups revealed the decreasing levels of density (73.54 ± 0.72%, 63.17 ± 1.77%, 61.79 ± 2.68%, respectively; vs. vehicle group, p < 0.05) throughout the entire experimental period. Additionally, the diminishing levels of density for peptidergic substance P (SP)-IR IENFs in paclitaxel groups were significantly shown (48.84 ± 1.74%, 30.02 ± 1.69%, 30.14 ± 0.37%, respectively; vs. vehicle group, p < 0.05). On the contrary, the density for peptidergic calcitonin gene-related peptide (CGRP)-IR IENFs in paclitaxel groups were revealed the similar decreasing levels (82.75 ± 0.91%, 84.34 ± 3.20%, 81.99 ± 0.25%, respectively; vs. vehicle group, p < 0.05). Linear regression analyses exhibited that densities of IENFs for PGP 9.5, SP, CGRP were correlated with withdrawal latencies (r2 = 0.77, p < 0.0001; r2 = 0.75, p < 0.0001; r2 = 0.28, p = 0.0001, respectively) and mechanical thresholds (r2 = 0.43, p < 0.0001; r2 = 0.73, p < 0.0001; r2 = 0.40, p < 0.0001, respectively). Therefore, the present results suggested that the development of neuropathic pain following paclitaxel injection induced the progressive degeneration of IENFs in skin and gave the evidence that the peptidergic IENFs may play an important role in therapeutic strategy of paclitaxe CIPN.