Mechanisms involved in the antinociception induced by systemic administration of guanosine in mice

Department of Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
British Journal of Pharmacology (Impact Factor: 4.84). 03/2010; 159(6):1247-63. DOI: 10.1111/j.1476-5381.2009.00597.x
Source: PubMed


It is well known that adenine-based purines exert multiple effects on pain transmission. However, less attention has been given to the potential effects of guanine-based purines on pain transmission. The aim of this study was to investigate the effects of intraperitoneal (i.p.) and oral (p.o.) administration of guanosine on mice pain models. Additionally, investigation into the mechanisms of action of guanosine, its potential toxicity and cerebrospinal fluid (CSF) purine levels were also assessed.
Mice received an i.p. or p.o. administration of vehicle (0.1 mM NaOH) or guanosine (up to 240 mg x kg(-1)) and were evaluated in several pain models.
Guanosine produced dose-dependent antinociceptive effects in the hot-plate, glutamate, capsaicin, formalin and acetic acid models, but it was ineffective in the tail-flick test. Additionally, guanosine produced a significant inhibition of biting behaviour induced by i.t. injection of glutamate, AMPA, kainate and trans-ACPD, but not against NMDA, substance P or capsaicin. The antinociceptive effects of guanosine were prevented by selective and non-selective adenosine receptor antagonists. Systemic administration of guanosine (120 mg x kg(-1)) induced an approximately sevenfold increase on CSF guanosine levels. Guanosine prevented the increase on spinal cord glutamate uptake induced by intraplantar capsaicin.
This study provides new evidence on the mechanism of action of the antinociceptive effects after systemic administration of guanosine. These effects seem to be related to the modulation of adenosine A(1) and A(2A) receptors and non-NMDA glutamate receptors.

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Available from: Elaine Elisabetsky, Oct 15, 2015
    • "An experimentally based hypothesis is that GUO caused an increase in extracellular ADO levels by competing with nucleoside transporter[19,20]. In fact, some of GUO's neuroprotective effects, but not all, are ADO receptor dependent181920212239]. Interestingly, radioactivity amounts were higher in brain structures following IP than IN[ 3 H]GUO solution administration . "
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    ABSTRACT: In addition to its intracellular roles, the nucleoside guanosine (GUO) also has extracellular effects that identify it as a putative neuromodulator signaling molecule in the central nervous system. Indeed, GUO can modulate glutamatergic neurotransmission, and it can promote neuroprotective effects in animal models involving glutamate neurotoxicity, which is the case in brain ischemia. In the present study, we aimed to investigate a new in vivo GUO administration route (intranasal, IN) to determine putative improvement of GUO neuroprotective effects against an experimental model of permanent focal cerebral ischemia. Initially, we demonstrated that IN [(3)H] GUO administration reached the brain in a dose-dependent and saturable pattern in as few as 5 min, presenting a higher cerebrospinal GUO level compared with systemic administration. IN GUO treatment started immediately or even 3 h after ischemia onset prevented behavior impairment. The behavior recovery was not correlated to decreased brain infarct volume, but it was correlated to reduced mitochondrial dysfunction in the penumbra area. Therefore, we showed that the IN route is an efficient way to promptly deliver GUO to the CNS and that IN GUO treatment prevented behavioral and brain impairment caused by ischemia in a therapeutically wide time window.
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    • "However, in relation to its antiepileptic/anticonvulsant effects, Guo (and GTP/GMP via degradation to Guo) [7] [126] might decrease excitability by the modulation of K + and Ca 2+ channel activity and may inhibit NMDA receptors via putative G i -protein-coupled Guo receptors similarly to A 1 receptors (Fig. 1). Although Guo may act independently of Ado and its receptors on astrocytic glutamate uptake and seizure activity [7] [34] [60] [121] [122], Guo also stimulates the release of Ado from astrocytes [9] [22] (Fig. 1) suggesting the involvement of the adenosinergic system in antiepileptic/anticonvulsant effect of Guo (e.g., via A 1 receptors), which is similar to the proposed mechanism of its antinociceptive effects [127] "
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    ABSTRACT: Adenosine (Ado) and some non-adenosine (non-Ado) nucleosides including inosine (Ino), guanosine (Guo) and uridine (Urd) are modulatory molecules in the central nervous system (CNS), regulating different physiological and pathophysiological processes in the brain such as sleep and epilepsy. Indeed, different drugs effective on adenosinergic system (e.g., Ado metabolism inhibitors, agonists and antagonists of Ado receptors) are being used in drug development for the treatment of epileptic disorders. Although (i) endogenous Ino, Guo and Urd showed anticonvulsant/antiepileptic effects (e.g., in quinolinic acid - induced seizures and in different epilepsy models such as hippocampal kindling models), and (ii) there is need to generate new and more effective antiepileptic drugs for the treatment of drug-resistant epilepsies, our knowledge about antiepileptic influence of non-Ado nucleosides is far from complete. Thus, in this review article, we give a short summary of anticonvulsant/antiepileptic effects and mechanisms evoked by Ino, Guo, and Urd. Finally, we discuss some non-Ado nucleoside derivatives and their structures, which may be candidates as potential antiepileptic agents.
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    ABSTRACT: Guanine-based purines have been traditionally studied as modulators of intracellular processes, mainly G-protein activity. However, more recently, several studies have shown that they exert a variety of extracellular effects not related to G-proteins, including trophic effects on neural cells, modulation of glutamatergic activity, behavioral effects and anticonvulsant activity. In this article, the putative effects of the guanine-based purines against seizures and neurotox-icity are reviewed. Current evidence suggests that guanine-based purines, especially guanosine, seem to be endogenous anticonvulsant substances, perhaps in a similar way to the adenine-based purines. Although studies addressing the mecha-nism of action of guanine-based purines are still lacking, their anticonvulsant activity is probably related to the modula-tion of several glutamatergic parameters, especially the astrocytic glutamate uptake. These findings point to the guanine-based purines as potential new targets for the development of novel drugs for neuroprotection and management of epi-lepsy.
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