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      Selective Ablation of Descending Serotonin from the Rostral Ventromedial Medulla Unmasks Its Pro-Nociceptive Role in Chemotherapy-Induced Painful Neuropathy

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          Abstract

          Purpose

          Chemotherapy-induced painful neuropathy (CIPN) is a severe adverse effect of many anti-neoplastic drugs that is difficult to manage. Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter in the rostral ventromedial medulla (RVM), which modulates descending spinal nociceptive transmission. However, the influence of the descending 5-HT from the RVM on CIPN is poorly understood. We investigated the role of 5-HT released from descending RVM neurons in a paclitaxel-induced CIPN rat model.

          Methods

          CIPN rat model was produced by intraperitoneally injecting of paclitaxel. Pain behavioral assessments included mechanical allodynia and heat hyperalgesia. 5-HT content was analyzed by high-performance liquid chromatography (HPLC). Western blot and immunohistochemistry were used to determine tryptophan hydroxylase (Tph) and c-Fos expression. The inhibitors p-chlorophenylalanine (PCPA) and SB203580 were administrated by stereotaxical RVM microinjection. Ondansetron was injected through intrathecal catheterization.

          Results

          The results demonstrated that Tph, the rate-limiting enzyme in 5-HT synthesis, was significantly upregulated in the RVM, and that spinal 5-HT release was increased in CIPN rats. Intra-RVM microinjection of Tph inhibitor PCPA significantly attenuated mechanical and thermal pain behavior through Tph downregulation and decreased spinal 5-HT. Intra-RVM administration of p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 alleviated paclitaxel-induced pain in a similar manner to PCPA. Intrathecal injection of ondansetron, a 5-HT3 receptor antagonist, partially reversed paclitaxel-induced pain, indicating that 5-HT3 receptors were involved in descending serotoninergic modulation of spinal pain processing.

          Conclusion

          The results suggest that activation of the p38 MAPK pathway in the RVM leads to increased RVM Tph expression and descending serotoninergic projection to the spinal dorsal horn and contributes to the persistence of CIPN via spinal 5-HT3 receptors.

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          Most cited references 50

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          A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel.

          Paclitaxel, an effective anti-neoplastic agent in the treatment of solid tumors, produces a dose-limiting painful peripheral neuropathy in a clinically significant number of cancer patients. Prior work has demonstrated paclitaxel-induced neurodegeneration and sensory loss in laboratory rodents. We describe here an experimental paclitaxel-induced painful peripheral neuropathy. Adult male rats were given four intraperitoneal injections on alternate days of vehicle or 0.5, 1.0, or 2.0 mg/kg of paclitaxel (Taxol). Behavioral tests for pain using mechanical and thermal stimuli applied to the tail and hind paws, and tests for motor performance, were taken before, during and after dosing for 22-35 days. All three doses of paclitaxel caused heat-hyperalgesia, mechano-allodynia, mechano-hyperalgesia, and cold-allodynia, but had no effect on motor performance. Neuropathic pain began within days and lasted for several weeks. We did not detect any dose-response relationship. Tests at the distal, mid, and proximal tail failed to show evidence of a length-dependent neuropathy. Vehicle control injections had no effect on any measure. No significant systemic toxicities were noted in the paclitaxel-treated animals. Light-microscopic inspection of the sciatic nerve (mid-thigh level), L4-L5 dorsal root ganglia, and dorsal and ventral roots, and the gray and white matter of the L4-L5 spinal cord, showed no structural abnormalities. Electron microscopic examination of the sciatic nerve (mid-thigh level) and the L4-L5 dorsal root ganglia and dorsal horns demonstrated no degeneration of myelinated and unmyelinated axons in the sciatic nerve and roots, but revealed endoneurial edema. This model may be useful in understanding a significant source of pain in cancer patients, and in finding ways to avoid the neurotoxicity that limits paclitaxel therapy.
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            Chemotherapy-Induced Peripheral Neuropathy: A Current Review.

            Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect experienced by patients receiving treatment for cancer. Approximately 30-40% of patients treated with neurotoxic chemotherapy will develop CIPN and there is considerable variability in its severity between patients. It is often sensory-predominant with pain and can lead to long-term morbidity in survivors. The prevalence and burden of CIPN late effects will likely increase as cancer survival rates continue to improve. In this review, we discuss the approach to peripheral neuropathy in patients with cancer and address the clinical phenotypes and pathomechanisms of specific neurotoxic chemotherapeutic agents. This article is protected by copyright. All rights reserved.
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              A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia

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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                jpr
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                24 November 2020
                2020
                : 13
                : 3081-3094
                Affiliations
                [1 ]Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University , Jinan 250021, People’s Republic of China
                [2 ]Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University , Jinan 250021, People’s Republic of China
                Author notes
                Correspondence: Xinhuan Niu; Mengyuan ZhangDepartment of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University , Jinan250021, People’s Republic of ChinaTel +86-53168776471; +86-53168776472 Email niuxhsph@163.com; zhangmysdfmu@163.com
                Article
                275254
                10.2147/JPR.S275254
                7700091
                © 2020 Liu 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: 9, References: 50, Pages: 14
                Categories
                Original Research

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