Intraepidermal nerve fiber loss corresponds to the development of Taxol-induced hyperalgesia and can be prevented by treatment with minocycline

Abstract

Loss of intraepidermal nerve fibers (IENFs) has been speculated to play a critical role in the development of various neuropathies. In this study, the density of IENFs were studied over time during the induction of Taxol-induced chemoneuropathy and compared with the changes in IENFs in animals co-treated with Taxol plus the protective agent minocycline. Rats were injected (i.p.) with 2mg/kg of Taxol every other day for 4 injections (Days 1, 3, 5, and 7). Minocycline (25 mg/kg) was given in a separate group of rats 24 hours prior to the first dose of Taxol and every day for the next 9 days (Days 0 through 9). Animals were tested for mechanical paw withdrawal thresholds prior to any drug administrations and again on Days 7, 14, and 30. Immunohistochemistry using the pan-neuronal marker PGP9.5 was performed on glabrous skin of the hind-paw foot pad to stain for IENFs also on Days 7, 14, and 30. The results show that Taxol-treated animals developed mechanical sensitivity and corresponding IENF loss. Animals receiving minocycline plus Taxol showed no hyperalgesia or loss of IENFs. This study confirms, for the first time, that a loss of IENFs occurs as a neuropathy develops, and further shows a protection against both IENF loss and hyperalgesia with minocycline treatment.

The Effect of Anakinra on Paclitaxel-Induced Peripheral Neuropathic Pain in Rats

“…It has been reported in several studies that paclitaxel is responsible for the development of peripheral neuropathic pain by increasing proinflammatory IL-1β expression (8)(9)(10)(11)(12). The IL-1β gene expression level increased in the paclitaxel group (PAC) compared to that in the HG and decreased in the groups in which anakinra was administered.…”

“…It has been found in numerous studies that reactive oxygen species (ROS) cause nerve injury-related pain and inflammatory pain (7). Paclitaxel has also been reported to activate proinflammatory cytokine expression (8)(9)(10)(11). Thus, the administration of paclitaxel results in the production of interleukin-1 beta (IL-1β) and other proinflammatory cytokines and their release from microglial cells.…”

Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes

“…A preclinical study of BCP indicated that the drug only attenuated pain behavior at an early stage (from d 4 to d 6) by inhibiting microglia [44] ; however, an increasing number of therapeutic effects of the agent have been identified. In studies of CIPN, minocycline prevented CIPN-related symptoms and the activation of astrocytes despite the lack of microglial activation indicators [16][17][18][19] . Nevertheless, minocycline also possesses neuroprotective roles [20,28,45,46] .…”

“…Minocycline, a second generation tetracycline antibiotic, selectively inhibits microglia. However, accumulating evidence indicates that it prevents chemotherapy-induced peripheral neuropathy (CIPN) via the inhibition of astrocytes [16][17][18][19] . Moreover, it has also been demonstrated that minocycline down-regulates NF-κB activity in several other cell lines [20,21] .…”

Axon Transport and Neuropathy

“…15 Because motor and sensory functions are often affected in a heterogeneous pattern, these agents appear to harm different types of neurons and in particular their axons (axonopathy) in humans with chemotherapy-induced PN 16,17 and in rodent models. 18 Moreover, as with DM-associated PN, the longest axons in the body appear to be preferentially vulnerable, and this may be due to their enhanced energy demand for transporting cellular constituents within long axons. Indeed, for >30 years axon transport abnormalities were recognized to have a role in PN caused by DM.…”