Agmatine reduces only peripheral-related behavioral signs, not the central signs, of morphine withdrawal in nNOS deficient transgenic mice

doi:10.1016/j.neulet.2003.10.010

Neuroscience Letters

Volume 354, Issue 2, 9 January 2004, Pages 153-157

https://doi.org/10.1016/j.neulet.2003.10.010 Get rights and content

Abstract

Agmatine inhibits morphine tolerance/dependence and potentiates morphine analgesia. This study was designed to investigate whether neuronal nitric oxide mediates the actions of agmatine in morphine dependence by using mice lacking a functional form of this enzyme. Mice received agmatine just after the morphine pellet implantation for 3 days twice daily or single injection 30 min before naloxone. In both genotypes treated for 3 days with morphine pellets, naloxone administration precipitated clear signs of withdrawal. Both acute and chronic administration of agmatine reduced withdrawal signs in wild type mice and reduced only peripheral signs of morphine dependence in neuronal nitric oxide synthase knockout mice. Withdrawal signs, that are related to central nervous system activity were not affected. These findings indicate that neuronal nitric oxide synthase partly mediates the effects of agmatine in morphine physical dependence.

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Cited by (39)

Agmatine prevents development of tolerance to anti-nociceptive effect of ethanol in mice
2022, Alcohol
Citation Excerpt :
We may recall that agmatine has been implicated in the process of drug addiction and associated complications. Agmatine diminishes the signs of ethanol, morphine, and nicotine withdrawal (Aricioglu et al., 2004; Kotagale et al., 2015, 2018; Uzbay et al., 1997, 2000). Further, it decreases ethanol, morphine, cocaine, and fentanyl self-administration in rats (Morgan et al., 2002; Su et al., 2009; Wade et al., 2008).
Drug tolerance is directly correlated with drug abuse and physical dependence. The development of tolerance is manifested as the decline in pharmacological responses of drugs following repeated administration of the constant dose. The present study evaluated the effect of agmatine in ethanol-induced anti-nociception and tolerance in the tail-flick assay in mice. In an acute protocol, ethanol (1 and 2 g/kg, i.p. [intraperitoneally]) and agmatine (20 and 40 μg/mouse, i.c.v. [intracerebroventricularly]) produced significant analgesic effects in mice, as was evident from the increased baseline tail-flick latency when tested 20 minutes after their administration. Agmatine in a per se non-effective dose (5 μg/mouse, i.c.v.), L-arginine (40 μg/mouse, i.c.v.), and arcaine (25 μg/mouse, i.c.v.) significantly potentiated the anti-nociceptive effect of ethanol. Blood ethanol analysis showed no significant differences in blood ethanol concentration between ethanol/saline- and ethanol/agmatine-treated mice, suggesting that the effects of agmatine were not due to any possible effects on the pharmacokinetics of ethanol. In a separate study, mice were injected with ethanol (2 g/kg, i.p., 12%) or saline (1 mL/kg, i.p.) once daily for 9 days. On days 1, 3, 5, 7, and 9 of the experiment, they were subjected to the tail-flick test. Agmatine (5–20 μg/mouse, i.c.v.), L-arginine (40 μg/mouse, i.c.v.), arcaine (25 μg/mouse, i.c.v.), aCSF (2 μL/mouse, i.c.v.), or saline (1 mL/kg, i.p.) was administered daily prior to the first daily ethanol or saline injections, and reaction latencies were determined in the tail-flick assay. Injections of agmatine, L-arginine, and arcaine prevented the development of tolerance to ethanol-induced analgesia. Given that agmatine and its endogenous modulation can prevent tolerance to the anti-nociceptive effects of ethanol, these data suggest it as a possible new therapeutic strategy for the treatment of alcohol use disorder and associated complications.
Agmatine, a metabolite of L-arginine, reverses scopolamine-induced learning and memory impairment in rats
2012, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Although it was reported that agmatine inhibits all three isoforms of nitric oxide synthase (NOS) (Galea et al., 1996), recently Mun et al. (2010) showed that it stimulates endothelial NOS in the rat brain. Several studies indicated that agmatine has a wide range of effects on central nervous system, such as its roles in morphine analgesia and morphine dependence (Aricioglu-Kartal and Uzbay, 1997; Aricioglu-Kartal and Regunathan, 2002; Aricioglu-Kartal et al., 2003; Aricioglu et al., 2004a, 2004b; Yananli et al., 2007), and antidepressant, anxiolytic (Aricioglu and Altunbaş, 2003; Zomkowski et al., 2002, 2004, 2005), antistress (Aricioglu et al., 2003a, 2003b, 2003c; Aricioglu and Regunathan, 2005), antinociceptive (Aricioglu et al., 2003a, 2003b, 2003c; Kolesnikov et al., 1996; Fairbanks et al., 2000; Santos et al., 2005), anticonvulsive (Aricioglu et al., 2003a, 2003b, 2003c; Demehri et al., 2003; Feng et al., 2005), antiproliferative, and neuroprotective (Gilad et al., 1996; Gilad and Gilad, 2000; Kim et al., 2004; Wang et al., 2006) effects in animal models. In contrast, the role of agmatine in learning and memory has not been extensively investigated.
Agmatine (l-amino-4-guanidino-butane), a metabolite of L-arginine through the action of arginine decarboxylase, is a novel neurotransmitter. In the present study, effects of agmatine on cognitive functions have been evaluated by using one trial step-down passive avoidance and three panel runway task. Agmatine (20, 40, 80 mg/kg i.p.) was administered either in the presence or absence of a cholinergic antagonist, scopolamine (1 mg/kg i.p.). Scopolamine significantly impaired learning and memory in both passive avoidance and three panel runway test. Agmatine did not affect emotional learning, working and reference memory but significantly improved scopolamine-induced impairment of learning and memory in a dose dependent manner. Our results indicate that agmatine, as an endogenous substance, may have an important role in modulation of learning and memory functions.
Supraspinally-administered agmatine attenuates the development of oral fentanyl self-administration
2008, European Journal of Pharmacology
The decarboxylation product of arginine, agmatine, has effectively reduced or prevented opioid-induced tolerance and dependence when given either systemically (intraperitoneally or subcutaneously) or centrally (intrathecally or intracerebroventricularly). Systemically administered agmatine also reduces the escalation phase of intravenous fentanyl self-administration in rats. The present study assessed whether centrally (intracerebroventricular, i.c.v.) delivered agmatine could prevent the development of fentanyl self-administration in mice. Mice were trained to respond under a fixed-ratio 1 (FR1) schedule for either fentanyl (0.7 μg/70 μl, p.o.) or food reinforcement. Agmatine (10 nmol/5 μl), injected i.c.v. 12–14 h before the first session and every other evening (12–14 h before session) for 2 weeks, completely attenuated oral fentanyl self-administration (but not food-maintained responding) compared to saline-injected controls. When agmatine was administered after fentanyl self-administration had been established (day 8) it had no attenuating effects on bar pressing. This dose of agmatine does not decrease locomotor activity as assessed by rotarod. The present findings significantly extend the previous observation that agmatine prevents opioid-maintained behavior to a chronic model of oral fentanyl self-administration as well as identifying a supraspinal site of action for agmatine inhibition of drug addiction.
Effects of intragastric agmatine on morphine-induced physiological dependence in beagle dogs and rhesus monkeys
2008, European Journal of Pharmacology
Our previous studies demonstrated that subcutaneous injection of agmatine inhibits tolerance to and physiological dependence on morphine in mice and rats. In the present study we further evaluated the effects of intragastric (i.g.) administration of agmatine on morphine-induced physiological dependence in mice, rats, beagle dogs and rhesus monkeys. When agmatine (5–40 mg/kg, i.g.) was co-administered with morphine during the development of morphine-induced physiological dependence, it inhibited the abstinent syndrome precipitated by naloxone in mice, rats and beagle dogs. In addition, agmatine (40 mg/kg, i.g.) inhibited the abstinent syndrome precipitated by naloxone in mice when it was administered on the test day. In naloxone precipitated and naturally abstinent morphine dependent model in rhesus monkeys, agmatine (40 or 80 mg/kg, i.g.) inhibited the development of physiological dependence when it was co-administered with morphine. After the development of morphine dependence, agmatine (80 mg/kg, i.g.) inhibited the naturally abstinent syndrome during the 7-d abstinent period. All these results suggested that intragastric administration of agmatine inhibits morphine-induced physiological dependence in animal models.
Agmatin and pain
2008, Douleurs
L’identification de l’agmatine (une polyamine endogène issue de la décarboxylation de la L-arginine), sa localisation dans le système nerveux central (SNC), son mode de synthèse, de stockage vésiculaire, de libération, de recapture et ses effets, en font un neurotransmetteur à part entière, impliqué dans la modulation et le traitement de l’information douloureuse. Son activité antihyperalgique et/ou antiallodynique, qui semble s’exercer dans des conditions de douleur soutenue et non aiguë, implique plusieurs mécanismes parmi lesquels la stimulation des récepteurs imidazolines et alpha2-adrénergiques, le blocage du récepteur canal N-méthyl-D-aspartate (et probablement d’autres récepteurs canaux) et l’inhibition de l’activité de la monoxyde d’azote synthase. L’agmatine peut même potentialiser l’effet analgésique de la morphine sans interagir directement avec les récepteurs opioïdes, prévenir la tolérance aux opiacés, s’opposer au développement de la dépendance et à l’apparition du syndrome de sevrage aux opiacés en modulant la signalisation intracellulaire sous-tendue par l’AMPc. La découverte de nouvelles cibles devrait permettre une meilleure compréhension de son rôle physiologique. Ces données expérimentales méritent d’être validées chez l’Homme, ce qui pourrait ouvrir de nouvelles voies thérapeutiques dans le traitement de la douleur chronique par l’agmatine, administrée seule ou en association avec de faibles doses d’analgésiques opiacés.
Agmatine is an amine synthesized by L-arginine decarboxylation found in the central nervous system (CNS). Because of its mode of synthesis, storage in synaptic vesicles, and release and uptake mechanisms, agmatine is an important neurotransmitter involved in pain processing. In animal models, agmatine has antihyperalgesic and antiallodynic activity in chronic rather than acute pain. Mechanisms involve the activation of imidazoline and alpha2-adrenergic receptors, blockade of N-methyl-D-aspartate receptor channels and other ligand-gated cationic channels, and inhibition of nitric oxide synthase activity. In animal studies, agmatine potentiates morphine analgesia without directly interacting with opioid receptors and reduces tolerance, dependence and withdrawal by interacting with intracellular cyclic adenosine monophosphate (cAMP) signaling. The discovery of new targets may provide a better understanding of its physiological role. These data allow consideration of agmatine as a potential therapeutic agent in the management of chronic pain alone or combined with low doses of opiate analgesics.
Effect of agmatine on brain l-citrulline production during morphine withdrawal in rats: A microdialysis study in nucleus accumbens
2007, Brain Research
Citation Excerpt :
Like other NOS inhibitors agmatine attenuates all of the behavioral signs of the NL-precipitated morphine withdrawal in rats. In a recent study, agmatine reduced only peripheral signs, but not the central signs of morphine physical dependence in neuronal NOS (nNOS) knockout mice indicating that functional nNOS is required for agmatine to reduce central signs (Arıcıoğlu et al., 2004). Since the effect of agmatine on morphine dependence requires NOS, the objectives of this study are (i) to follow up NO formation by means of l-citrulline production during morphine withdrawal and (ii) to compare the effects of classical NOS inhibitor l-nitro-arginine methyl ester (l-NAME) with agmatine on NO production indirectly in the nucleus accumbens core region (NAcc) of morphine-dependent rats by using microdialysis.
Agmatine, an endogenous nitric oxide (NO) synthase inhibitor and ligand for imidazoline receptors, has been previously shown to prevent morphine dependence in rats. The present study was designed to investigate NO formation in nucleus accumbens core region (NAcc) during naloxone (NL)-precipitated morphine withdrawal in rats treated with agmatine or l-NAME by using intracerebral microdialysis in freely moving rats, through measuring extracellular l-citrulline concentrations, an indirect sign of NO production since equal amounts of l-citrulline and NO are produced from l-arginine. l-Citrulline levels in the NAcc core did not change following administration of agmatine (40 mg/kg i.p.) or l-NAME (100 mg/kg i.p.) in control rats. Both agmatine and l-NAME attenuated withdrawal symptoms of morphine in NL (2 mg/kg i.p.)-precipitated withdrawal. l-Citrulline levels showing the release of NO increased in morphine-dependent rats during NL-precipitated withdrawal. Agmatine and l-NAME treatments significantly suppressed the increase in l-citrulline levels compared to physiological saline-treated rats in this setting. The results suggest that the release of l-citrulline in NAcc may be involved in the processes of morphine withdrawal and agmatine as an endogenous inhibitor of NO synthase may be one of the factors involved in the changes in the physiology and behavioral state during opioid withdrawal and may have pharmacological importance.

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Agmatine reduces only peripheral-related behavioral signs, not the central signs, of morphine withdrawal in nNOS deficient transgenic mice

Abstract

Cell

Mol. Gen. Metab.

Neurosci. Lett.

Eur. J. Pharmacol.

Neurosci. Biobehav. Rev.

Brain Res.

Trends Pharmacol. Sci.

Biochem. Pharmacol.

Brain Res.

Brain Res.

Eur. J. Pharmacol.

Neuropsychopharmacology

Inhibition of morphine withdrawal syndrome by a nitric oxide synthase inhibitor, NG-nitro-l-arginine methyl ester

Life Sci.

Effect of chronic morphine treatment on the biosynthesis of agmatine in rat brain and other tissues

Life Sci.

Inhibitory effect of agmatine on naloxone-precipitated abstinence syndrome

Life Sci.

Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies

Psychopharmacology

Up-regulation of neuronal NO synthase immunoreactivity in opiate dependence and withdrawal

Psychopharmacology