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      Antinociceptive Effect of the Citrus Flavonoid Eriocitrinon Postoperative Pain Conditions

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      Journal of Pain Research

      Dove

      flavanones, surgical pain, analgesia, incisional pain, natural products

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          Abstract

          Background

          Postoperative pain remains a major clinical problem as there are limited analgesic strategies that have been proven to be effective in preventing and relieving this type of pain. Natural products, including flavonoids, have distinct pharmacological properties and play an important role in the discovery of analgesic drugs.

          Materials and Methods

          In this study, the flavonoid eriocitrin (eriodictyol 7- O-rutinoside), which is the main flavonoid in lemon fruit ( Citrus limon), was mechanistically investigated for its prospective antinociceptive effect in a mouse model of postoperative pain. The antinociceptive property was evaluated by utilizing both tonic (acetic acid-induced writhing behavior) and phasic (hot-plate) nociception modalities. The hindpaw incisional surgery was performed and hyperalgesia was assessed using von Frey filaments.

          Results

          The tested doses of eriocitrin significantly attenuated ( P<0.01, P<0.001) the chemically-induced tonic visceral nociception (5, 10, 15, and 30 mg/kg) and acute phasic thermal nociception (10, 15, and 30 mg/kg). A significant dose-dependent reduction in the incisional nociceptive hyperalgesia was exhibited by eriocitrin, with a marked antinociception observed at doses of 15 mg/kg ( P<0.05 during 30–60 minutes) and 30 mg/kg ( P<0.05, P<0.01 during 30–120 minutes).

          Conclusion

          The antinociceptive effect of eriocitrin (30 mg/kg) was strongly blocked by the antagonists of the opioid receptor, naltrexone, and GABA A receptor, bicuculline, thereby suggesting the involvement of opioidergic and GABAergic mechanisms in the nociception, reducing proclivity of eriocitrin during transmission of incisional nociception. These results concluded that eriocitrin has a potent antinociceptive effect in postoperative pain conditions, probably mediated through opioid and GABA A receptors.

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          Most cited references 70

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          Basic opioid pharmacology: an update

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            Postoperative pain control.

            The effective relief of pain is of the utmost importance to anyone treating patients undergoing surgery. Pain relief has significant physiological benefits; hence, monitoring of pain relief is increasingly becoming an important postoperative quality measure. The goal for postoperative pain management is to reduce or eliminate pain and discomfort with a minimum of side effects. Various agents (opioid vs. nonopioid), routes (oral, intravenous, neuraxial, regional) and modes (patient controlled vs. "as needed") for the treatment of postoperative pain exist. Although traditionally the mainstay of postoperative analgesia is opioid based, increasingly more evidence exists to support a multimodal approach with the intent to reduce opioid side effects (such as nausea and ileus) and improve pain scores. Enhanced recovery protocols to reduce length of stay in colorectal surgery are becoming more prevalent and include multimodal opioid sparing regimens as a critical component. Familiarity with the efficacy of available agents and routes of administration is important to tailor the postoperative regimen to the needs of the individual patient.
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              The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy

              Background Oxaliplatin, the third-generation platinum compound, has evolved as one of the most important therapeutic agents in colorectal cancer chemotherapy. The main limiting factor in oxaliplatin treatment is painful neuropathy that is difficult to treat. This side effect has been studied for several years, but its full mechanism is still inconclusive, and effective treatment does not exist. Data suggest that oxaliplatin’s initial neurotoxic effect is peripheral and oxidative stress-dependent. A spinal target is also suggested in its mechanism of action. The flavonoids rutin and quercetin have been described as cell-protecting agents because of their antioxidant, antinociceptive, and anti-inflammatory actions. We proposed a preventive effect of these agents on oxaliplatin-induced painful peripheral neuropathy based on their antioxidant properties. Methods Oxaliplatin (1 mg/kg, i.v.) was injected in male Swiss mice, twice a week (total of nine injections). The development of sensory alterations, such as thermal and mechanical allodynia, was evaluated using the tail immersion test in cold water (10°C) and the von Frey test. Rutin and quercetin (25-100 mg/kg, i.p.) were injected 30 min before each oxaliplatin injection. The animals’ spinal cords were removed for histopathological and immunohistochemical evaluation and malondialdehyde assay. Results Oxaliplatin significantly increased thermal and mechanical nociceptive response, effects prevented by quercetin and rutin at all doses. Fos immunostaining in the dorsal horn of the spinal cord confirmed these results. The oxidative stress assays mainly showed that oxaliplatin induced peroxidation in the spinal cord and that rutin and quercetin decreased this effect. The flavonoids also decreased inducible nitric oxide synthase and nitrotyrosine immunostaining in the dorsal horn of the spinal cord. These results suggest that nitric oxide and peroxynitrite are also involved in the neurotoxic effect of oxaliplatin and that rutin and quercetin can inhibit their effect in the spinal cord. We also observed the preservation of dorsal horn structure using histopathological analyses. Conclusions Oxaliplatin induced painful peripheral neuropathy in mice, an effect that was prevented by rutin and quercetin. The mechanism of action of oxaliplatin appears to be, at least, partially oxidative stress-induced damage in dorsal horn neurons, with the involvement of lipid peroxidation and protein nitrosylation.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                JPR
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                22 April 2020
                2020
                : 13
                : 805-815
                Affiliations
                [1 ]Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University , Makkah 21955, Saudi Arabia
                Author notes
                Correspondence: Saad Alghamdi Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura, University , PO Box 715, Makkah21955, Saudi ArabiaTel +966 505502114 Email ssalghamdi@uqu.edu.sa
                Article
                250391
                10.2147/JPR.S250391
                7183786
                © 2020 Alghamdi.

                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: 6, References: 78, Pages: 11
                Categories
                Original Research

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