Agmatine: Biological Role and Therapeutic Potentials in Morphine Analgesia and Dependence

Overview

Journal AAPS J

Specialty Pharmacology

Date 2006 Oct 10

PMID 17025265

Citations 11

Authors

Soundar Regunathan

Affiliations

Soon will be listed here.

Abstract

Agmatine is an amine that is formed by decarboxylation of L-arginine by the enzyme arginine decarboxylase (ADC) and hydrolyzed by the enzyme agmatinase to putrescine. Agmatine binds to several target receptors in the brain and has been proposed as a novel neuromodulator. In animal studies, agmatine potentiated morphine analgesia and reduced dependence/withdrawal. While the exact mechanism is not clear, the interactions with N-methyl-D-aspartate (NMDA) receptors, alpha2-adrenergic receptors, and intracellular cyclic adenosine monophosphate (cAMP) signaling have been proposed as possible targets. Like other monoamine transmitter molecules, agmatine is rapidly metabolized in the periphery and has poor penetration into the brain, which limits the use of agmatine itself as a therapeutic agent. However, the development of agmatinase inhibitors will offer a useful method to increase endogenous agmatine in the brain as a possible therapeutic approach to potentiate morphine analgesia and reduce dependence/withdrawal. This review provides a succinct discussion of the biological role/therapeutic potential of agmatine during morphine exposure/pain modulation, with an extensive amount of literature cited for further details.

Citing Articles

Agmatine reduces alcohol drinking and produces antinociceptive effects in rodent models of alcohol use disorder.

Lopez M, Davis E, Cucinello-Ragland J, Regunathan S, Edwards S, Becker H Alcohol. 2023; 109:23-33.

PMID: 36709008 PMC: 10175169. DOI: 10.1016/j.alcohol.2023.01.003.

Agmatine Alleviates Cisplatin-Induced Ototoxicity by Activating PI3K/AKT Signaling Pathway.

Zhang Y, Lv Z, He Q eNeuro. 2022; 9(2).

PMID: 35256453 PMC: 8957377. DOI: 10.1523/ENEURO.0434-21.2022.

Agmatine requires GluN2B-containing NMDA receptors to inhibit the development of neuropathic pain.

Peterson C, Kitto K, Verma H, Pflepsen K, Delpire E, Wilcox G Mol Pain. 2021; 17:17448069211029171.

PMID: 34210178 PMC: 8255568. DOI: 10.1177/17448069211029171.

Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels.

Nag A, Kurushima Y, Bowyer R, Wells P, Weiss S, Pietzner M Hum Mol Genet. 2020; 29(5):864-875.

PMID: 31960908 PMC: 7104674. DOI: 10.1093/hmg/ddz308.

Agmatine preferentially antagonizes GluN2B-containing N-methyl-d-aspartate receptors in spinal cord.

Waataja J, Peterson C, Verma H, Goracke-Postle C, Seguela P, Delpire E J Neurophysiol. 2018; 121(2):662-671.

PMID: 30427758 PMC: 6397392. DOI: 10.1152/jn.00172.2018.

References

Zomkowski A, Rosa A, Lin J, Santos A, Calixto J, Severo Rodrigues A . Evidence for serotonin receptor subtypes involvement in agmatine antidepressant like-effect in the mouse forced swimming test. Brain Res. 2004; 1023(2):253-63. DOI: 10.1016/j.brainres.2004.07.041. View

Hansson B, HOKFELT B . Changes in blood pressure, plasma catecholamines and plasma renin activity during and after treatment with tiamenidine and clonidine. Br J Clin Pharmacol. 1981; 11(1):73-7. PMC: 1401688. DOI: 10.1111/j.1365-2125.1981.tb01105.x. View

Gatti P, Hill K, da Silva A, NORMAN W, GILLIS R . Central nervous system site of action for the hypotensive effect of clonidine in the cat. J Pharmacol Exp Ther. 1988; 245(1):373-80. View

Sauve Y, Reader T . Effects of alpha-methyl-p-tyrosine on monoamines and catecholamine receptors in rat cerebral cortex and neostriatum. Neurochem Res. 1988; 13(9):807-15. DOI: 10.1007/BF00970747. View

Copeland Jr R, Pradhan S, Dillon-Carter O, Chuang D . Rebound increase of basal cAMP level in NG108-15 cells during chronic morphine treatment: effects of naloxone and chloramphenicol. Life Sci. 1989; 44(16):1107-16. DOI: 10.1016/0024-3205(89)90338-x. View

Reynolds I . Arcaine uncovers dual interactions of polyamines with the N-methyl-D-aspartate receptor. J Pharmacol Exp Ther. 1990; 255(3):1001-7. View

Guitart X, Nestler E . Second messenger and protein phosphorylation mechanisms underlying opiate addiction: studies in the rat locus coeruleus. Neurochem Res. 1993; 18(1):5-13. DOI: 10.1007/BF00966918. View

Vanderah T, Wild K, TAKEMORI A, Sultana M, Portoghese P, Bowen W . Modulation of morphine antinociception by swim-stress in the mouse: involvement of supraspinal opioid delta-2 receptors. J Pharmacol Exp Ther. 1993; 267(1):449-55. View

Hieble J, Kolpak D . Mediation of the hypotensive action of systemic clonidine in the rat by alpha 2-adrenoceptors. Br J Pharmacol. 1993; 110(4):1635-9. PMC: 2175845. DOI: 10.1111/j.1476-5381.1993.tb14012.x. View

10.

Li G, Regunathan S, Barrow C, Eshraghi J, Cooper R, Reis D . Agmatine: an endogenous clonidine-displacing substance in the brain. Science. 1994; 263(5149):966-9. DOI: 10.1126/science.7906055. View

11.

Trujillo K, Akil H . Inhibition of opiate tolerance by non-competitive N-methyl-D-aspartate receptor antagonists. Brain Res. 1994; 633(1-2):178-88. DOI: 10.1016/0006-8993(94)91538-5. View

12.

Mehta C, Strada S . Effects of acute and continuous administration of morphine on the cyclic AMP response induced by norepinephrine in rat brain slices. Life Sci. 1994; 55(1):35-42. DOI: 10.1016/0024-3205(94)90079-5. View

13.

Aricioglu F, Means A, Regunathan S . Effect of agmatine on the development of morphine dependence in rats: potential role of cAMP system. Eur J Pharmacol. 2004; 504(3):191-7. PMC: 2923207. DOI: 10.1016/j.ejphar.2004.10.011. View

14.

Santos A, Gadotti V, Oliveira G, Tibola D, Paszcuk A, Neto A . Mechanisms involved in the antinociception caused by agmatine in mice. Neuropharmacology. 2005; 48(7):1021-34. DOI: 10.1016/j.neuropharm.2005.01.012. View

15.

Askalany A, Yamakura T, Petrenko A, Kohno T, Sakimura K, Baba H . Effect of agmatine on heteromeric N-methyl-D-aspartate receptor channels. Neurosci Res. 2005; 52(4):387-92. DOI: 10.1016/j.neures.2005.05.002. View

16.

Feng Y, Leblanc M, Regunathan S . Agmatine reduces extracellular glutamate during pentylenetetrazole-induced seizures in rat brain: a potential mechanism for the anticonvulsive effects. Neurosci Lett. 2005; 390(3):129-33. PMC: 2920494. DOI: 10.1016/j.neulet.2005.08.008. View

17.

Iyo A, Zhu M, Ordway G, Regunathan S . Expression of arginine decarboxylase in brain regions and neuronal cells. J Neurochem. 2006; 96(4):1042-50. PMC: 2921170. DOI: 10.1111/j.1471-4159.2005.03544.x. View

18.

Aricioglu F, Korcegez E, Bozkurt A, Ozyalcin S . Effect of agmatine on acute and mononeuropathic pain. Ann N Y Acad Sci. 2004; 1009:106-15. DOI: 10.1196/annals.1304.010. View

19.

Morgan A, Campbell U, Fons R, Carroll M . Effects of agmatine on the escalation of intravenous cocaine and fentanyl self-administration in rats. Pharmacol Biochem Behav. 2002; 72(4):873-80. DOI: 10.1016/s0091-3057(02)00774-8. View

20.

Aricioglu-Kartal F, Regunathan S . Effect of chronic morphine treatment on the biosynthesis of agmatine in rat brain and other tissues. Life Sci. 2002; 71(14):1695-701. DOI: 10.1016/s0024-3205(02)01911-2. View