Abstract
The effects of agmatine, which is an endogenous polyamine metabolite formed by decarboxylation of L-arginine, and a combination of agmatine and morphine on tail-flick test have been investigated in mice. Adult male Swiss–Webster mice were used in the study. Agmatine (10, 20 and 40 mg/kg), clonidine (0.15 mg/kg), yohimbine (0.625 and 1.25 mg/kg), or saline were injected into mice intraperitoneally. Morphine (1 and 2 mg/kg) was given subcutaneously. Agmatine alone did not produce any significant change on radiant tail-flick latencies, but it potentiated significantly and dose-dependently morphine-induced (1 mg/kg) analgesia. The potentiating effect of agmatine (40 mg/kg) on morphine-induced analgesia was blocked completely by yohimbine (0.625 mg/kg), a selective α2-adrenoceptor antagonist, pretreatment. Clonidine (0.15 mg/kg), an α2-adrenergic receptor agonist, caused a significant increase of the tail-flick latencies of the mice. Yohimbine (0.625 mg/kg) also blocked clonidine-induced analgesia. In addition, yohimbine (0.625 mg/kg) was ineffective on the tail-flick test and did not produce any significant change on the morphine-induced analgesia. Our results indicate that cotreatment of agmatine with morphine produces antinociceptive enhancement via an α2-adrenergic receptor-mediated mechanism and agmatine–morphine combination may be an effective therapeutic strategy for medical treatment of pain.
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References
Adams ML, Kalicki JM, Meyer ER, Cicero J . (1993): Inhibition of morphine withdrawal syndrome by a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester. Life Sci 52: PL245–PL249
Adams ML, Sewing BN, Chen J, Meyer EL, Cicero T . (1995): Nitric oxide-related agents alter alcohol withdrawal in male rats. Alcohol Clin Exp Res 19: 195–199
Akil H, Mayer J . (1972): Antagonism of stimulation-produced analgesia by p-CPA, a serotonin synthesis inhibitor. Brain Res 44: 692–697
Aricioglu-Kartal F, Uzbay IT . (1997): Inhibitory effect of agmatine on naloxone-precipitated abstinence syndrome in morphine-dependent rats. Life Sci 61: 1775–1781
Bradley KJ, Headley PM . (1997): Effect of agmatine on spinal nociceptive reflexes: Lack of interaction with alpha 2-adrenoceptor or μ-opioid receptor mechanisms. Eur J Pharmacol 331: 133–138
Browning S, Lawrence D, Livingston A, Morris B . (1982): Interactions of drugs activate at opiate receptors and drugs active at alpha 2-receptors on various test systems. Br J Pharmacol 77: 487–491
Currie PJ, Wilson LM . (1992): Yohimbine attenuates clonidine-induced feeding and macronutrient selection in genetically obese (ob/ob) mice. Pharmacol Biochem Behav 43: 1039–1046
Dambisya YM, Chan K, Wong CL . (1991): Role of adrenoceptors in the potentiation of opioid antinociception by ephedrine and phenylpropanolamine in mice. Psychopharmacology 105: 563–567
D'Amour FE, Smith DL . (1941): A method for determining loss of pain sensation. J Pharmacol Exp Ther 72: 74–79
Denizbasi A, Ozyazgan S, Eskazan E . (1999): The effect of tizanidine on maximal electroshock seizures (MES) in mice. Gen Pharmacol 32: 513–516
Fairbanks CA, Posthumus IJ, Kitto KF, Stone LS, Wilcox GL . (2000): Moxonidine, a selective imidazoline/alpha(2) adrenergic receptor agonist, synergizes with morphine and deltorphin II to inhibit substance P-induced behavior in mice. Pain 84: 13–20
Fairbanks CA, Wilcox GL . (1997): Acute tolerance to spinally administered morphine compares mechanistically with chronically induced morphine tolerance. J Pharmacol Exp Ther 282: 1408–1417
Fairbanks CA, Wilcox GL . (1999): Spinal antinociceptive synergism between morphine and clonidine persists in mice made acutely or chronically tolerant to morphine. J Pharmacol Exp Ther 288: 1107–1116
Galea E, Regunathan S, Elipoulos V, Feinstein DL, Reis DJ . (1996): Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochem J 316(pt 1):247–249
Gonzalez C, Regunathan S, Reis DJ, Estrada C . (1996): Agmatine, an endogenous modulator of noradrenergic neurotransmission in the rat tail artery. Br J Pharmacol 119: 677–684
Horváth G, Kekesi G, Dobos I, Szikszay M, Klimscha W, Benedek G . (1999): Effect of intrathecal agmatine on inflammation-induced thermal hyperalgesia in rats. Eur J Pharmacol 368: 197–204
Jurkewicz NH, Garcez do Carmo L, Hirata H, da Costa Santos W, Jurkiewicz A . (1996): Functional properties of agmatine in rat vas deferens. Eur J Pharmacol 307: 299–304
Kihara T, Kaneto H . (1986): Important role of adrenergic function in the development of analgesic tolerance to morphine in mice. Japan J Pharmacol 42: 419–423
Kolesnikov Y, Jain S, Pasternak GW . (1996): Modulation of opioid analgesia by agmatine. Eur J Pharmacol 296: 17–22
Kotlinska J, Liljequist S . (1996): Oral administration of glycine and polyamine receptor antagonists blocks ethanol withdrawal seizures. Psychopharmacology 127: 238–244
Li G, Regunathan S, Barrow CJ, Eshraghi J, Cooper R, Reis DJ . (1994): Agmatine: An endogenous clonidine-displacing substance in the brain. Science 263: 966–969
Lortie MJ, Novotny WF, Peterson OW, Vallon V, Malvey K, Mendonca M, Satriano J, Insel P, Thomson SC, Blantz RC . (1996): Agmatine, a bioactive metabolite of arginine. J Clin Invest 97: 413–420
Ossipov MH, Suarez LJ, Spaulding TC . (1989): Antinociceptive interactions between alpha 2-adrenergic and opiate agonists at the spinal level in rodents. Anesth Analg 68: 194–200
Paalzow L . (1974): Analgesia produced by clonidine in mice and rats. J Pharm Pharmacol 26: 361–363
Piletz JE, Chikkala DN, Ernsberger P . (1995): Comparison of the properties of agmatine and endogenous clonidine-displacing substance at imidazoline and alpha 2-adrenergic receptors. J Pharmacol Exp Ther 272: 581–587
Pineda J, Ruiz-Ortega JA, Martin-Ruiz R, Ugedo L . (1996): Agmatine does not have activity at α2-adrenoceptors which modulate the firing rate of locus coeruleus neurones: An electrophysiological study in rat. Neurosci Lett 219: 103–106
Pinthong D, Wright IK, Hanmer C, Millns P, Mason R, Kendall DA, Wilson VG . (1995a): Agmatine recognizes α2-adrenoceptor binding sites but neither activates nor inhibits α2-adrenoceptors. Naunyn-Schmiedeberg's Arch Pharmacol 351: 10–16
Pinthong D, Hussain JF, Kendall DA, Wilson WG . (1995b): Comparison of the interaction of agmatine and crude methanolic extracts of bovine lung and brain with α2-adrenoceptor binding sites. Br J Pharmacol 115: 689–695
Regunathan S, Reis DJ . (1996): Imidazoline receptors and their endogenous ligands. Ann Rev Pharmacol Toxicol 36: 511–544
Reis DJ, Regunathan S . (1998a): Agmatine: An endogenous ligand at imidazoline receptors may be a novel neurotransmitter in brain. J Auton Nerv Sys 72: 80–85
Reis DJ, Regunathan S . (1998b): Agmatine: A novel transmitter? Adv Pharmacol 42: 645–649
Roerig SC . (1995): Decreased spinal morphine/clonidine antinociceptive synergism in morphine-tolerant mice. Life Sci 56: PL115–PL122
Roerig SC, Lei S, Kitto K, Hylden JLK, Wilcox GL . (1992): Spinal interactions between opioid and noradrenergic agonists in mice: Multiplicitivity involves δ and α2 receptors. J Pharmacol Exp Ther 262: 365–374
Rossetti Z, Carboni S . (1995): Ethanol withdrawal associated with increased extracellular glutamate in the rat striatum. Eur J Pharmacol 283: 177–183
Tabor CW, Tabor H . (1984): Polyamines. Ann Rev Biochem 53: 749–790
Thorat SN, Barjavel MJ, Matwyshn GA, Bhargava HN . (1994): Comparative effects of NG-monomethyl-L-arginine and MK-801 on the abstinence syndrome in morphine-dependent mice. Brain Res 642: 153–159
Trujillo KA, Akil H . (1991): Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251: 85–87
Uzbay IT, Erden BF, Tapanyiğit EE, Kayaalp SO . (1997): Nitric oxide synthase inhibition attenuates signs of ethanol withdrawal in rats. Life Sci 61: 2197–2209
Uzbay IT, Çınar MG, Aytemir M, Tuglular I . (1999): Analgesic effect of tianeptine in mice. Life Sci 64: 1313–1319
Uzbay IT, Yeşilyurt Ö, Çelik T, Ergün H, Işımer A . (2000): Effects of agmatine on ethanol withdrawal syndrome in rats. Behav Brain Res 107: 153–159
Vaupel DB, Kimes AS, London ED . (1997): Further in vivo studies on attenuating morphine withdrawal: Isoform selective nitric oxide synthase inhibitors differ in efficacy. Eur J Pharmacol 324: 11–20
Wigdor S, Wilcox GL . (1987): Central and systemic morphine-induced antinociception in mice: Contribution of descending serotonergic and noradrenergic pathways. J Pharmacol Exp Ther 242: 90–95
Yang XC, Reis DJ . (1999): Agmatine selectively blocks the N-methyl-D-aspartate subclass of glutamate receptor channels in rat hippocampal neurons. J Pharmacol Exp Ther 288: 544–549
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The authors thank Dr. Zafer Gören and Dr. Ongun Onaran for their valuable supports to the study.
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Yesilyurt, Ö., Uzbay, I. Agmatine Potentiates the Analgesic Effect of Morphine by an α2-Adrenoceptor-Mediated Mechanism in Mice. Neuropsychopharmacol 25, 98–103 (2001). https://doi.org/10.1016/S0893-133X(00)00245-1
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DOI: https://doi.org/10.1016/S0893-133X(00)00245-1
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