Protection against oxaliplatin-induced mechanical hyperalgesia and intraepidermal nerve fiber loss by minocycline

Treatment with the chemotherapeutic agent oxaliplatin produces a robust painful neuropathy similar to various other neuropathic conditions which result in loss of nerve fibers innervating the skin. This loss of intraepidermal nerve fibers (IENFs) appears to play an important role in neuropathy, but has yet to be investigated in oxaliplatin-induced neuropathic pain. For this study, mechanical hyperalgesia and IENF density were measured in rats receiving oxaliplatin, given at a dosage of 2 mg/kg every other day for four injections. The immunomodulatory agent minocycline (25 mg/kg) was also administered and was given 24 h prior to the first dose of oxaliplatin and continued throughout oxaliplatin treatment. Immunohistochemistry using the pan-neuronal marker PGP9.5 was used to investigate IENF densities in hind paw skin on Day 15 and Day 30. The results show that a robust mechanical sensitivity developed in oxaliplatin treated animals, as did a pronounced decrease in epidermal nerve fibers, and these outcomes were effectively prevented by minocycline treatment. This is the first study to show changes in IENF density in oxaliplatin treated animals, and confirm not only a relationship between IENF loss and hypersensitivity but also prevention of both with minocycline treatment.

Research highlights
► Oxaliplatin often produces peripheral neuropathy.
► Similar neuropathies are accompanied by intraepidermal nerve fiber loss.
► We show mechanical hypersensitivity and loss of nerve fibers with oxaliplatin.
► Both outcomes were prevented by minocycline treatment.