Intraperitoneal administration of ascorbic acid attenuates hyperalgesia in a rat model of neuropathic pain

Sepide Saffarpour, Shakira Ghafour, Farinaz Nasirinezhad


Background: Ascorbic acid is a well-known antioxidant but its antinociceptive effect on chronic pain is not known. The aim of this study is to evaluate the analgesic effect of intraperitoneal administration of different doses of ascorbic acid in a peripheral neuropathic pain model.

Methods: To investigate the efficacy of ascorbic acid on neuropathic pain, male rats were allocated to 5 acute administration and 2 chronic administration groups. Pain induced by chronic constriction injury of sciatic nerve (CCI). Different amount of ascorbic acid (1, 3, 5 and 10 mg/kg) and normal saline were injected in acute protocol (single injection two weeks after CCI). In addition, ascorbic acid was administrated with dose of 3 mg/kg (daily injection for three weeks; chronic administration). Hyperalgesia and allodynia were assessed.

Results: Chronic intraperitoneal injection of 3 mg/kg ascorbic acid for 3 weeks increase pain threshold from the second week after CCI. Acute administration of 1 mg/kg ascorbic acid did not produce any changes in pain threshold of neuropathic rats but acute injection of 5 and 10 mg/kg, significantly alleviate pain 30 minutes after injection in the second week following CCI. Similar result observed in chronic administration of ascorbic acid.

Conclusion: These data suggest that ascorbic acid produces analgesia in neuropathic rats.


Ascorbate; Hyperalgesia; Allodynia; Chronic Constriction Injury

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Grünewald RA. Ascorbic acid in the brain. Brain Res Rev. 1993;18(1):123-33.

Harrison FE, May JM. Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2. Free Radic Biol Med. 2009;46(6):719-30.

Wilson JX. Regulation of vitamin c transport. Annu Rev Nutr. 2005;25(1):105-25.

Savini I, Rossi A, Pierro C, Avigliano L, Catani MV. SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids. 2007;34(3):347-55.

DiLabio GA, Wright JS. Hemiketal formation of dehydroascorbic acid drives ascorbyl radical anion disproportionation. Free Radic Biol Med. 2000;29(5):480-5.

Pastore P, Rizzetto T, Curcuruto O, Cin MD, Zaramella A, Marton D. Characterization of dehydroascorbic acid solutions by liquid chromatography/mass spectrometry. Rapid Commun Mass Spectrom. 2001;15(22):2051-7.

Jackson TS, Xu A, Vita JA, Keaney JF. Ascorbate Prevents the Interaction of Superoxide and Nitric Oxide Only at Very High Physiological Concentrations. Circ Res. 1998;83(9):916-22.

Sandstrom MI, Rebec GV. Extracellular ascorbate modulates glutamate dynamics: role of behavioral activation. BMC Neurosci. 2007;8(1):32.

Rebec GV, Witowski SR, Sandstrom MI, Rostand RD, Kennedy RT. Extracellular ascorbate modulates cortically evoked glutamate dynamics in rat striatum. Neurosci Lett. 2005;378(3):166-70.

Ciani E, Grøneng L, Voltattorni M, Rolseth V, Contestabile A, Paulsen RE. Inhibition of free radical production or free radical scavenging protects from the excitotoxic cell death mediated by glutamate in cultures of cerebellar granule neurons. Brain Res. 1996;728(1):1-6.

Zhou H-Y, Chen S-R, Pan H-L. Targeting N -methyl- D -aspartate receptors for treatment of neuropathic pain. Expert Rev Clin Pharmacol. 2011;4(3):379-88.

Majewska MD, Bell JA, London ED. Regulation of the NMDA receptor by redox phenomena: inhibitory role of ascorbate. Brain Res. 1990;537(1-2):328-32.

Todorovic SM, Jevtovic-Todorovic V, Meyenburg A, Mennerick S, Perez-Reyes E, Romano C, et al. Redox Modulation of T-Type Calcium Channels in Rat Peripheral Nociceptors. Neuron. 2001;31(1):75-85.

Duconge J, Miranda-Massari JR, Gonzalez MJ, Jackson JA, Warnock W, NH R. Pharmacokinetics of vitamin C: insights into the oral and intravenous administration of ascorbate. P R Health Sci J. 2008;27(1):7-19.

Engelhart MJ. Dietary Intake of Antioxidants and Risk of Alzheimer Disease. JAMA. 2002;287(24):3223-32239.

Nagayama H, Hamamoto M, Ueda M, Nito C, Yamaguchi H, Katayama Y. The Effect of Ascorbic Acid on the Pharmacokinetics of Levodopa in Elderly Patients with Parkinson Disease. Clin Neuropharmacol. 2004;27(6):270-3.

Casani S, Gómez-Pastor R, Matallana E, Paricio N. Antioxidant compound supplementation prevents oxidative damage in a Drosophila model of Parkinson's disease. Free Radic Biol Med. 2013;61:151-60.

Rebec GV. Dysregulation of Corticostriatal Ascorbate Release and Glutamate Uptake in Transgenic Models of Huntington's Disease. Antioxid Redox Signal. 2013;19(17):2115-28.

Schencking M, Vollbracht C, Weiss G, Lebert J, Biller A, Goyvaerts B, et al. Intravenous Vitamin C in the treatment of shingles: Results of a multicenter prospective cohort study. Med Sci Monit. 2012;18(4):CR215-CR24.

Shibuya N, Humphers JM, Agarwal MR, Jupiter DC. Efficacy and Safety of High-dose Vitamin C on Complex Regional Pain Syndrome in Extremity Trauma and Surgery—Systematic Review and Meta-Analysis. J Foot Ankle Surg. 2013;52(1):62-6.

Chen J-Y, Chang C-Y, Feng P-H, Chu C-C, So EC, Hu M-L. Plasma Vitamin C Is Lower in Postherpetic Neuralgia Patients and Administration of Vitamin C Reduces Spontaneous Pain but Not Brush-evoked Pain. Clin J Pain. 2009;25(7):562-9.

Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988;33(1):87-107.

Hama A, Borsook D. Behavioral and pharmacological characterization of a distal peripheral nerve injury in the rat. Pharmacol Biochem Behav. 2005;81(1):170-81.

Kirk G, White J, McKie L, Stevenson M, Young I, Clements W, et al. Combined Antioxidant Therapy Reduces Pain and Improves Quality of Life in Chronic Pancreatitis. J Gastrointest Surg. 2006;10(4):499-503.

Okubo K, Nakanishi H, Matsunami M, Shibayama H, Kawabata A. Topical application of disodium isostearyl 2-O-L-ascorbyl phosphate, an amphiphilic ascorbic acid derivative, reduces neuropathic hyperalgesia in rats. Br J Pharmacol. 2012;166(3):1058-68.

Du WD, Yuan ZR, Sun J, Tang JX, Cheng AQ, Shen DM, et al. Therapeutic efficacy of high-dose vitamin C on acute pancreatitis and its potential mechanisms. World J Gastroenterol. 2003;9(11):2565-9.

Yeom CH, Jung GC, Song KJ. Changes of terminal cancer patients' health-related quality of life after high dose vitamin C administration. J Korean Med Sci. 2007;22(1):7-11.

Sommer C, Schäfers M. Painful mononeuropathy in C57BL/Wld mice with delayed Wallerian degeneration: differential effects of cytokine production and nerve regeneration on thermal and mechanical hypersensitivity. Brain Res. 1998;784(1-2):154-62.

McLean NA, Popescu BF, Gordon T, Zochodne DW, Verge VMK. Delayed Nerve Stimulation Promotes Axon-Protective Neurofilament Phosphorylation, Accelerates Immune Cell Clearance and Enhances Remyelination In Vivo in Focally Demyelinated Nerves. PLoS One. 2014;9(10):e110174.

Polidori MC, Mecocci P, Levine M, Frei B. Short-term and long-term vitamin C supplementation in humans dose-dependently increases the resistance of plasma to ex vivo lipid peroxidation. Arch Biochem Biophys. 2004;423(1):109-15.

Rosa KA, Gadotti VM, Rosa AO, Rodrigues ALS, Calixto JB, Santos ARS. Evidence for the involvement of glutamatergic system in the antinociceptive effect of ascorbic acid. Neurosci Lett. 2005;381(1-2):185-8.

Nasirinezhad F, Saffarpour S. Involvement of NMDA Receptors in Antinociceptive Effect of Ascorbic Acid in a Neuropathic Pain Model. Razi J Med Sci. 2009;60(15):193-204.

Sekiguchi F, Kawabata A. T-type Calcium Channels: Functional Regulation and Implication in Pain Signaling. J Pharmacol Sci. 2013;122(4):244-50.

Terada Y, Kawabata A. H2S and Pain: A Novel Aspect for Processing of Somatic, Visceral and Neuropathic Pain Signals. Handb Exp Pharmacol. 2015;230:217-30.

Seol M, Kuner T. Ionotropic glutamate receptor GluA4 and T-type calcium channel Cav3.1 subunits control key aspects of synaptic transmission at the mouse L5B-POm giant synapse. Eur J Neurosci. 2015;42(12):3033-44.

Nazıroğlu M, Dikici DM, Dursun Ş. Role of Oxidative Stress and Ca2+ Signaling on Molecular Pathways of Neuropathic Pain in Diabetes: Focus on TRP Channels. Neurochem Res. 2012;37(10):2065-75.

Nelson MT, Joksovic PM, Su P, Kang HW, Van Deusen A, Baumgart JP, et al. Molecular Mechanisms of Subtype-Specific Inhibition of Neuronal T-Type Calcium Channels by Ascorbate. J Neurosci. 2007;27(46):12577-83.

Nasirinezhad F, Safarpour S. Antinociceptive effect of ascorbic acid and involvement of nitric oxide in a chronic pain model. Pharmaceut Sci 2010;16(3):157-68.

Scheid T, Bosco LD, Guedes RP, Pavanato MA, Belló-Klein A, Partata WA. Sciatic Nerve Transection Modulates Oxidative Parameters in Spinal and Supraspinal Regions. Neurochem Res. 2013;38(5):935-42.

Goecks CSB, Horst A, Moraes MS, Scheid T, Kolberg C, Belló-Klein A, et al. Assessment of Oxidative Parameters in Rat Spinal Cord After Chronic Constriction of the Sciatic Nerve. Neurochem Res. 2012;37(9):1952-8.

Ranjan A, Theodore D, Haran RP, Chandy MJ. Ascorbic acid and focal cerebral ischaemia in a primate model. Acta Neurochir (Wien). 1993;123(1-2):87-91.


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