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      The Antiallodynic Effect of Nefopam on Vincristine-Induced Neuropathy in Mice

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          Chemotherapy-induced neuropathic pain is a disabling condition following cancer treatment. Vincristine has more neurotoxicity than other vinca alkaloid agents. This study evaluated the correlation of different doses of nefopam with antiallodynic effects in a mouse vincristine neuropathy model.


          A peripheral neuropathic mouse model was made by intraperitoneal injection of vincristine (0.1 mg/kg/day; 5-day-on, 2-day-off schedule over 12 days). After the development of allodynia, mice were injected intraperitoneally with 0.9% normal saline (NS group) or various doses (10, 30, 60 mg/kg) of nefopam (Nefopam group). We examined allodynia using von Frey hairs pre-administration and at 30, 60, 90, 120, 180, 240 mins, and 24 hrs after drug administration. We also measured the neurokinin-1 receptor concentrations in the spinal cord to confirm the antiallodynic effect of nefopam after drug administration.


          The peripheral neuropathic mouse model showed prominent mechanical allodynia. Intraperitoneal nefopam produced a clear dose-dependent increase in paw withdrawal threshold compared with pre-administration values and versus the NS group. The concentration of neurokinin-1 receptor was significantly decreased in the Nefopam group (P<0.05).


          Intraperitoneally administered nefopam yielded a dose-dependent attenuation of mechanical allodynia and decreased neurokinin-1 receptor concentration, suggesting that the neurokinin-1 receptor is involved in the antiallodynic effects of nefopam in vincristine neuropathy.

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          Most cited references 37

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          Mechanisms in cancer-chemotherapeutic drugs-induced peripheral neuropathy.

          Anti-cancer drugs such as vincristine, paclitaxel, oxaliplatin, cisplatin and bortezomib are well reported to exert direct and indirect effects on sensory nerves to alter the amplitude of action potential, conduction velocity and induce pain. It results in patient suffering and also limits the treatment with potentially useful anticancer drugs. The different scientists have worked in this area to explore the mechanisms responsible for its pathogenesis. Anti-cancer agents activate plasma membrane localized ion channels on dorsal root ganglia and dorsal horn neurons including sodium, calcium, potassium, glutamate activated NMDA receptors to alter cytosolic ionic mileu particularly intracellular calcium that trigger secondary changes to induce neuropathic pain. These may include opening of mPTP pore on mitochondria to induce intracellular calcium release; activation of protein kinase C; phosphorylation of TRPV; activation of calpases/calpains; generation of nitric oxide and free radicals to induce cytotoxicity to axons and neuronal cell bodies. Furthermore, the inflammatory process initiated in glial cells and macrophages also trigger changes in the sensory neurons to alter nociceptive processing. The present review elaborates the role of all these individual targets in the pathogenesis of anticancer agents-induced neuropathic pain to develop effective therapeutic modalities for pain management. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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            Intraepidermal nerve fiber loss corresponds to the development of taxol-induced hyperalgesia and can be prevented by treatment with minocycline.

            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 (Bristol-Myers Squibb, NY, USA)-induced chemoneuropathy and compared with the changes in IENFs in animals co-treated with Taxol plus the protective agent minocycline. Rats were injected (intraperitoneally) with 2mg/kg of Taxol every other day for four injections (day 1, 3, 5, and 7). Minocycline (25mg/kg) was given in a separate group of rats 24h prior to the first dose of Taxol and every day for the next 9days (day 0 through 9). Animals were tested for mechanical paw withdrawal thresholds prior to any drug administrations and again on day 7, 14, and 30. Immunohistochemistry using the pan-neuronal marker protein gene product 9.5 was performed on glabrous skin of the hind-paw foot pad to stain for IENFs also on day 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 progression of Taxol-induced mechanical hypersensitivity coincides with loss of intraepidermal nerve fibers, and the hyperalgesia and nerve fiber loss were prevented with minocycline treatment. Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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              An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat.

              Paclitaxel (Taxol) is a frontline antineoplastic agent used to treat a variety of solid tumors including breast, ovarian, or lung cancer. The major dose limiting side effect of paclitaxel is a peripheral sensory neuropathy that can last days to a lifetime. To begin to understand the cellular events that contribute to this neuropathy, we examined a marker of cell injury/regeneration (activating transcription factor 3; ATF3), macrophage hyperplasia/hypertrophy; satellite cell hypertrophy in the dorsal root ganglia (DRG) and sciatic nerve as well as astrocyte and microglial activation within the spinal cord at 1, 4, 6 and 10 days following intravenous infusion of therapeutically relevant doses of paclitaxel. At day 1 post-infusion, there was an up-regulation of ATF3 in a subpopulation of large and small DRG neurons and this up-regulation was present through day 10. In contrast, hypertrophy of DRG satellite cells, hypertrophy and hyperplasia of CD68(+) macrophages in the DRG and sciatic nerve, ATF3 expression in S100beta(+) Schwann cells and increased expression of the microglial marker (CD11b) and the astrocyte marker glial fibrillary acidic protein (GFAP) in the spinal cord were not observed until day 6 post-infusion. The present results demonstrate that using the time points and markers examined, DRG neurons show the first sign of injury which is followed days later by other neuropathological changes in the DRG, peripheral nerve and dorsal horn of the spinal cord. Understanding the cellular changes that generate and maintain this neuropathy may allow the development of mechanism-based therapies to attenuate or block this frequently painful and debilitating condition.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                07 February 2020
                : 13
                : 323-329
                [1 ]Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University, School of Medicine , Seoul, Korea
                [2 ]Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, College of Medicine , Seoul, Korea
                Author notes
                Correspondence: Hue Jung Park Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea , Seoul06591, KoreaTel +82 2-2258-6157Fax +82 2-537-1951 Email huejung@catholic.ac.kr
                © 2020 Lee et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 3, References: 42, Pages: 7
                Original Research

                Anesthesiology & Pain management

                vincristine, allodynia, neuropathy, neurokinin-1, nefopam, mice


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