Effect of agmatine on the development of morphine dependence in rats: potential role of cAMP system

Abstract

Agmatine is an endogenous amine derived from arginine that potentiates morphine analgesia and blocks symptoms of naloxone-precipitated morphine withdrawal in rats. In this study, we sought to determine whether treatment with agmatine during the development of morphine dependence inhibits the withdrawal symptoms and that the effect is mediated by cAMP system. Exposure of rats to morphine for 7 days resulted in marked naloxone-induced withdrawal symptoms and agmatine treatment along with morphine significantly decreasing the withdrawal symptoms. The levels of cAMP were markedly increased in morphine-treated rat brain slices when incubated with naloxone and this increase was significantly reduced in rats treated with morphine and agmatine. The induction of tyrosine hydroxylase after morphine exposure was also reduced in locus coeruleus when agmatine was administered along with morphine. We conclude that agmatine reduces the development of dependence to morphine and that this effect is probably mediated by the inhibition of cAMP signaling pathway during chronic morphine exposure.

Agmatine Potentiates Morphine-Induced Conditioned Place Preference in Mice: Modulation by Alpha(2)-Adrenoceptors

“…Acute administration of low dose of agmatine prevents tolerance following chronic morphine treatment for 10 days (Kolesnikov et al, 1996). Agmatine prevents naloxone-precipitated abstinence syndrome in morphine-dependent rats and attenuates all of the signs of morphine withdrawal syndrome dose-dependently (Aricioglu-Kartal and Uzbay, 1997;Uzbay et al, 2000;Li et al, 2002;Aricioglu et al, 2004). Exposure of rats to morphine for 3 days is shown to decrease the levels of agmatine in the liver, kidney, brain, aorta, and intestine; also, precipitation of withdrawal syndrome by injecting naloxone further decreases agmatine levels in these tissues, providing evidence that endogenous agmatine may play an important role in regulating morphine tolerance, dependence, and withdrawal symptoms (Aricioglu-Kartal and Regunathan, 2002).…”

“…The beneficial potentiating effects of agmatine on morphine analgesia (Kolesnikov et al, 1996;Yesilyurt and Uzbay, 2001;Ruiz-Durantez et al, 2003) are clearly documented. Agmatine has been shown to reduce the development of dependence to morphine (Aricioglu et al, 2004) and attenuates the contractile response to naloxone in morphine-dependent guinea-pig ileum (Aricioglu et al, 2003). This latter effect is partly abolished by pretreatment with yohimbine and is almost completely abolished by idazoxan.…”

Expression and localization of an agmatinase-like protein in the rat brain

“…It is also considered a neurotransmitter/neuromodulator because it is synthesized in the brain, stored in synaptic vesicles in regionally selective neurons, accumulated by uptake and released by depolarization (Reis and Regunathan 2000). Among other actions, agmatine binds with high affinity to a2-adrenergic and imidazoline receptors (Piletz et al 1995), regulates the release of catecholamines from presynaptic terminals and adrenal chromaffin cells, and potentiates opioid analgesia (Aricioglu et al 2004). In addition, injection of agmatine in animals produces anticonvulsant, antineurotoxic and antidepressant-like actions (Halaris and Plietz 2007).…”

Expression of arginine decarboxylase in brain regions and neuronal cells

“…Agmatine has been shown to modulate transmitter/hormone release, including norepinephrine, vasopressin and glutamate probably acting at voltage-gated calcium channels (Li et al 1994;Kalra et al 1995;Wang et al 2002). The pharmacological actions of agmatine include the potentiation of morphine analgesia and anti-nociceptive effects in various pain models (Kolesnikov et al 1996;Fairbanks et al 2000;Gilad and Gilad 2000;Yu et al 2000;Onal and Soykan 2001), anti-inflammatory effects Regunathan and Piletz 2003), protection against ischemic neuronal injury Gilad and Gilad 2000;Yu et al 2000;Zhu et al 2003), anti-seizure activity (Aricioglu et al 2003;Su et al 2004;Feng et al 2005) and reduction of tolerance and withdrawal symptoms to morphine (Kolesnikov et al 1996;Li et al 1999;Aricioglu et al 2004). While the physiological role of endogenous agmatine in these actions is not clear, it is evident that ADC may play a crucial role in determining the availability of agmatine in neuronal cells.…”