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2016 | 76 | 2 |

Tytuł artykułu

Inhibition of neuronal and inducible nitric oxide synthase does not affect the analgesic effects of NMDA antagonists in visceral inflammatory pain

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Previously we described the antinociceptive effect of magnesium sulfate and dizocilpine (MK-801) in the visceral and somatic rat models of pain. In the somatic model of pain, we established the influence of selective inhibitors of neuronal and inducible nitric oxide synthase on the antihyperalgesic effects of magnesium sulfate and dizocilpine. Therefore, the objective of the present study was to determine in the rat model of visceral pain whether same mechanisms are involved in the antinociceptive action of magnesium sulfate and dizocilpine. Analgesic activity was assessed using the acetic acid-induced writhing test in rats. Subcutaneous injection of either magnesium sulfate (15 mg/kg) or dizocilpine (0.01 mg/kg) decreased the number of writhes by about 60 and 70%, respectively. The role of nitric oxide on the effects of magnesium sulfate and dizocilpine was evaluated using selective inhibitor of neuronal [N-ω-Propyl-L-arginine hydrochloride (L-NPA)] and inducible [S-methylisothiourea (SMT)] nitric oxide synthase, which per se did not affect the number of writhes. We observed that the antinociceptive effect of magnesium sulfate or dizocilpine did not change in the presence of L-NPA (2 and 10 mg/kg, i.p.) and SMT (0.015 and 10 mg/kg, i.p.). We conclude that, nitric oxide produced by neuronal and inducible nitric oxide synthase does not modulate the effects of magnesium sulfate and dizocilpine in the visceral inflammatory model of pain in the rat.

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  • Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
  • Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
  • Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia


  • Abacioğlu N, Tunçtan B, Akbulut E, Cakici I (2000) Participation of the components of L-arginine/nitric oxide/cGMP cascade by chemicallyinduced abdominal constriction in the mouse. Life Sci 67: 1127–1137.
  • Al-Mamun Mst, Hajera khatun Md, Rafikul Islam, Laizuman Nahar K, M Shams-ud-doha, Farhana Alam Ripa (2011) Evaluation of CNS depressant and analgesic activities of methanol extract of Piper longum Linn. Leaves. Int J Pharm Sci Res 2: 2874–2879.
  • Alva-Sanchez C, Rodriguez A, Villanueva I, Anguiano B, Aceves C, PachecoRosado J (2014) The NMDA receptor antagonist MK-801 abolishes the increase in both p53 and Bax/Bcl2 index induced by adult onset hypothyroidism in rat. Acta Neurobiol Exp (Wars) 74: 111–117.
  • Assi AA (2001) The influence of divalent cations on the analgesic effect of opioid and non-opioid drugs. Pharmacol Res 43: 521–529.
  • Bhat AS, Tandan SK, Kumar D, Krishna V, Prakash VR (2008) The interaction between inhibitors of nitric oxide synthase and cyclooxygenase in formalininduced pain in mice: an isobolographic study. Anesth Analg 106: 978–984.
  • Bulutcu F, Dogrul A, Güç MO (2002) The involvement of nitric oxide in the analgesic effects of ketamine. Life Sci 71: 841–853.
  • Burns GA, Stephens KE, Benson JA (1994) Expression of mRNA for the N-methyl-D-aspartate (NMDAR1) receptor by the enteric neurons of the rat. Neurosci Lett 170: 87–90.
  • Cervero F (1985) Visceral nociception: peripheral and central aspects of visceral nociceptive systems. Philos Trans R Soc Lond B Biol Sci 308: 325–337.
  • Eid SR, Crown ED, Moore EL, Liang HA, Choong KC, Dima S, Henze DA, Kane SA, Urban MO (2008) HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity. Mol Pain 4: 48.
  • Fawcett WJ, Haxby EJ, Male DA (1999) Magnesium: physiology and pharmacology. Br J Anaesth 83: 302–320.
  • Freire MA, Guimarães JS, Leal WG, Pereira A (2009) Pain modulation by nitric oxide in the spinal cord. Front Neurosci 3: 175–181.
  • García MD, Fernández MA, Alvarez A, Saenz MT (2004) Antinociceptive and anti-inflammatory effect of the aqueous extract from leaves of Pimenta racemosa var. ozua (Mirtaceae). J Ethnopharmacol 91: 69–73.
  • Herroeder S, Schönherr ME, De Hert SG, Hollmann MW (2011) Magnesium- -essentials for anesthesiologists. Anesthesiology 114: 971–993.
  • Jahangiri L, Kesmati M, Najafzadeh H (2013) Evaluation of analgesic and anti-inflammatory effect of nanoparticles of magnesium oxide in mice with and without ketamine. Eur Rev Med Pharmacol Sci 17: 2706–2710.
  • Kovacic P, Somanathan R (2010) Clinical physiology and mechanism of dizocilpine (MK-801): electron transfer, radicals, redox metabolites and bioactivity. Oxid Med Cell Longev 3: 13–22.
  • LaBuda CJ, Koblish M, Tuthill P, Dolle RE, Little PJ (2006) Antinociceptive activity of the selective iNOS inhibitor AR-C102222 in rodent models of inflammatory, neuropathic and post-operative pain. Eur J Pain 10: 505–512.
  • Le Bars D, Gozariu M, Cadden SW (2001) Animal models of nociception. Pharmacol Rev 53: 597–652.
  • Li J, McRoberts JA, Nie J, Ennes HS, Mayer EA (2004) Electrophysiological characterization of N-methyl-D-aspartate receptors in rat dorsal root ganglia neurons. Pain 109: 443–452.
  • Ludbrook GL, James MF, Upton RN (1999) The effect of magnesium sulfate on cerebral blood flow velocity, cardiovascular variables, and arterial carbon dioxide tension in awake sheep. J Neurosurg Anesthesiol 11: 96–101.
  • Mogil JS, Kest B, Sadowski B, Belknap JK (1996) Differential genetic mediation of sensitivity to morphine in genetic models of opiate antinociception: influence of nociceptive assay. J Pharmacol Exp Ther 276: 532–544.
  • Mohammad FK, Al-Baggou BKh, Naser AS (2012) Antinociception by metoclopramide, ketamine and their combinations in mice. Pharmacol Rep 64(2): 299–304.
  • Mueller RA, Hunt R (1998) Antagonism of ketamine-induced anesthesia by an inhibitor of nitric oxide synthesis: a pharmacokinetic explanation. Pharmacol Biochem Behav 60: 15–22.
  • Øey I (1998) Ketamine analgesia, NMDA receptors and the gates of perception. Acta Anaesthesiol Scand 42: 747–749.
  • Pereira LM, Lima-Júnior RC, Bem AX, Teixeira CG, Grassi LS, Medeiros RP, Marques-Neto RD, Callado RB, Aragão KS, Wong DV, Vale ML, Brito GA, Ribeiro RA (2013) Blockade of TRPA1 with HC-030031 attenuates visceral nociception by a mechanism independent of inflammatory resident cells, nitric oxide and the opioid system. Eur J Pain 17: 223–233.
  • Reichert JA, Daughters RS, Rivard R, Simone DA (2001) Peripheral and preemptive opioid antinociception in a mouse visceral pain model. Pain 89: 221–227.
  • Salińska E, Lazarewicz JW (1995) Modulation of NMDA receptor-mediated release of [3H]arachidonate in hippocampal slices of immature rats. Acta Neurobiol Exp (Wars) 55: 11–21.
  • Słomka M, Kuszczyk M, Łazarewicz JW, Makarewicz D (2014) NMDA receptor antagonists MK-801 and memantine induce tolerance to oxygen and glucose deprivation in primary cultures of rat cerebellar granule cells. Acta Neurobiol Exp (Wars) 74: 396–404.
  • Srebro DP, Vučković SM, Savić Vujović KR, Prostran MS (2014b) Nitric oxide synthase modulates the antihyperalgesic effect of the NMDA receptor antagonist MK-801 on Carrageenan-induced inflammatory pain in rats. Tohoku J Exp Med 234: 287–293.
  • Srebro DP, Vučković SM, Savić Vujović KR, Prostran MŠ (2015) TRPA1, NMDA receptors and nitric oxide mediate mechanical hyperalgesia induced by local injection of magnesium sulfate into the rat hind paw. Physiol Behav 139: 267–273.
  • Srebro DP, Vučković S, Vujović KS, Prostran M (2014a) Anti-hyperalgesic effect of systemic magnesium sulfate in carrageenan-induced inflammatory pain in rats: influence of the nitric oxide pathway. Magnes Res 27: 77–85.
  • Standley CA, Batia L, Yueh G (2006) Magnesium sulfate effectively reduces blood pressure in an animal model of preeclampsia. J Matern Fetal Neonatal Med 19: 171–176.
  • Strigo IA, Duncan GH, Bushnell MC, Boivin M, Wainer I, Rodriguez Rosas ME, Persson J (2005) The effects of racemic ketamine on painful stimulation of skin and viscera in human subjects. Pain 113: 255–264.
  • Suardíaz M, Estivill-Torrús G, Goicoechea C, Bilbao A, Rodríguez de Fonseca F (2007) Analgesic properties of oleoylethanolamide (OEA) in visceral and inflammatory pain. Pain 133: 99–110.
  • Tobin JR, Martin LD, Breslow MJ, Traystman RJ (1994) Selective anesthetic inhibition of brain nitric oxide synthase. Anesthesiology 81: 1264–1269.
  • Varga G, Erces D, Fazekas B, Fülöp M, Kovács T, Kaszaki J, Fülöp F, Vécsei L, Boros M (2010) N-Methyl-D-aspartate receptor antagonism decreases motility and inflammatory activation in the early phase of acute experimental colitis in the rat. Neurogastroenterol Motil 22: 217–225.
  • Vučković S, Srebro D, Savić Vujovic K, Prostran M (2015) The antinociceptive effects of magnesium sulfate and MK-801 in visceral inflammatory pain model: The role of NO/cGMP/K(+)ATP pathway. Pharm Biol 53: 1621–1627.
  • Willert RP, Woolf CJ, Hobson AR, Delaney C, Thompson DG, Aziz Q (2004) The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate receptor. Gastroenterology 126: 683–692.
  • Yamanaka M, Taniguchi W, Nishio N, Hashizume H, Yamada H, Yoshida M, Nakatsuka T (2015) In vivo patch-clamp analysis of the antinociceptive actions of TRPA1 activation in the spinal dorsal horn. Mol Pain 21: 11–20.
  • Zhuo M, Meller ST, Gebhart GF (1993) Endogenous nitric oxide is required for tonic cholinergic inhibition of spinal mechanical transmission. Pain 54: 71–78.

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