Minocycline Prevents the Development of Mechanical Allodynia in Mouse Models of Vincristine-Induced Peripheral Neuropathy.

Vincristine is an antineoplastic substance that is part of many chemotherapy regimens, used especially for the treatment of a variety of pediatric cancers including leukemias and brain tumors. Unfortunately, many vincristine-treated patients develop peripheral neuropathy, a side effect characterized by sensory, motoric, and autonomic symptoms. The sensory symptoms include pain, in particular hypersensitivity to light touch, as well as loss of sensory discrimination to detect vibration and touch. The symptoms of vincristine-induced neuropathy are only poorly controlled by currently available analgesics and therefore often necessitate dose reductions or even cessation of treatment. The aim of this study was to identify new therapeutic targets for the treatment of vincristine-induced peripheral neuropathy (VIPN) by combining behavioral experiments, histology, and pharmacology after vincristine treatment. Local intraplantar injection of vincristine into the hind paw caused dose- and time-dependent mechanical hypersensitivity that developed into mechanical hyposensitivity at high doses, and lead to a pronounced, dose-dependent infiltration of immune cells at the site of injection. Importantly, administration of minocycline effectively prevented the development of mechanical hypersensitivity and infiltration of immune cells in mouse models of vincristine induce peripheral neuropathy (VIPN) based on intraperitoneal or intraplantar administration of vincristine. Similarly, Toll-like receptor 4 knockout mice showed diminished vincristine-induced mechanical hypersensitivity and immune cell infiltration, while treatment with the anti-inflammatory meloxicam had no effect. These results provide evidence for the involvement of Toll-like receptor 4 in the development of VIPN and suggest that minocycline and/or direct Toll-like receptor 4 antagonists may be an effective preventative treatment for patients receiving vincristine.

Transcriptomics in pain research: insights from new and old technologies.

Despite significant advances in our understanding of the molecular basis of pain, the precise contributions of individual genes to our perception of this primal sensation remains incomplete. However, transcriptomic studies - providing a snapshot of the mRNA expression of a given cell or tissue - have considerably increased insight into the gene expression fingerprint of specific sensory neuronal subtypes, as well as gene expression changes that occur in diverse pathologies associated with pain. Moreover, transcriptomic studies have accelerated the identification of venom-derived peptides that may provide novel leads for the development of analgesics. This review discusses some of the key techniques, insights and limitations of transcriptomic studies that have contributed to pain research and highlights how the application of transcriptomics can be used to accelerate analgesic venom peptide drug discovery.