Guanosine prevents thermal hyperalgesia in a rat model of peripheral mononeuropathy.
ABSTRACT It is well known that adenine-based purines exert multiple effects on pain transmission. Less attention has been given, however, to the antinociceptive effects of guanine-based purines. The aim of this study was to investigate the effects of intraperitoneal administration of guanosine on a rat model of peripheral mononeuropathy. Additionally, investigation of the mechanism of action of guanosine, its general toxicity and measurements of central nervous system purine levels were performed. Rats received an intraperitoneal administration of vehicle (0.1 mM NaOH) or guanosine (up to 120 mg.kg(-1)) in an acute or chronic regimen. Guanosine significantly reduced thermal hyperalgesia on the ipsilateral side of the sciatic nerve ligation. Additionally, guanosine prevented locomotor deficits and body weight loss induced by the mononeuropathy. Acute systemic administration of guanosine caused an approximately 11-fold increase on central nervous system guanosine levels, but this effect was not observed after chronic treatment. Chronic guanosine administration prevented the increase on cortical glutamate uptake but not the decrease in spinal cord glutamate uptake induced by the mononeuropathy. No significant general toxicity was observed after chronic exposure to guanosine. This study provides new evidence on the mechanism of action of guanine-based purines, with guanosine presenting antinociceptive effects against a chronic pain model. PERSPECTIVE: This study provides a new role for guanosine: chronic pain modulation. Guanosine presents as a new target for future drug development and might be useful for treatment of neuropathic pain.
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ABSTRACT: Guanine nucleotides were shown to alter N-methyl-d-aspartate (NMDA) receptor-effector coupling by competitive antagonism at the glutamate binding site, rather than via interaction with an intracellularly located GTP-binding protein. Thus, in contrast to known G-protein linked receptors, micromolar concentrations of guanine nucleotides and their analogs decreased both agonist [( 3H]glutamate) and antagonist [( 3H]-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid binding to the NMDA receptor complex. The most potent compound, the GDP analog guanosine-5'-O-(2-thiodiphosphate) (GDP beta S), was studied in detail. GDP beta S exhibited almost 200-fold selectivity for the glutamate recognition site vs. the strychnine-insensitive glycine binding site. IC50 values were 2.7 +/- 1.4 and 484 +/- 97 microM, respectively. GDP beta S also inhibited N-[1-(2-thienyl)cyclohexyl-3H]piperidine binding (IC50 was 28.0 +/- 3.7 microM) in an NMDA-reversible fashion. [3H]-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid saturation binding studies revealed an increase in Kd from 263 +/- 49 (control) to 552 +/- 134 nM (8 microM GDP beta S) without any change in maximum binding (4.94 +/- 0.34 and 5.19 +/- 0.58 pmol/mg of protein, respectively). GDP beta S was also a competitive inhibitor of the following NMDA-stimulated responses: elevation of cyclic GMP in neonatal rat cerebellar slices, release of preloaded [3H]norepinephrine from superfused rat hippocampal slices and elevation of cytosolic calcium concentration in fura-2-loaded cultured rat forebrain neurons. IC50 values were 78.4, 53.4 and 1.6 microM, respectively. Finally, GDP beta S resembled known NMDA receptor antagonists in its ability to block NMDA receptor-induced seizures after i.c.v. administration.(ABSTRACT TRUNCATED AT 250 WORDS)Journal of Pharmacology and Experimental Therapeutics 08/1989; 250(1):162-9. · 3.89 Impact Factor
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ABSTRACT: Functional loss after spinal cord injury (SCI) is caused, in part, by demyelination of axons surviving the trauma. Administration of guanosine (8 mg/kg/day, i.p.) for 7 consecutive days, starting 5 weeks after moderate SCI in rats, improved locomotor function and spinal cord remyelination. Myelinogenesis was associated with an increase in the number of mature oligodendrocytes detected in guanosine-treated spinal cord sections in comparison with controls. These data indicate that guanosine-induced remyelination resulted, at least in part, from activation of endogenous oligodendrocyte lineage cells. These findings may have significant implications for chronic demyelinating diseases.Neuroreport 01/2004; 14(18):2463-7. · 1.40 Impact Factor
Article: Purines and neutrophil leukocytes[show abstract] [hide abstract]
ABSTRACT: 1.1. Adenosine is a normal constituent of all body fluids and its levels are raised, for example, by hypoxia and ischemia. In addition, both adenosine and ATP can be released by endothelial cells and neutrophils in response to physiologic stimulation.2.2. Human neutrophil leukocytes possess multiple adenosine receptors and P2 purinoceptors.3.3. ATP can increase intracellular Ca2+ levels in neutrophils, cause degranulation and enzyme release, potentiate the oxidative burst and enhance their adhesion to the endothelium. ATP is broken down to adenosine by ecto-enzymes. Via A1 receptors, adenosine can increase neutrophil chemotaxis and, via A2A receptors, it can decrease the oxidative burst, degranulation and adhesion to endothelium.4.4. Adenosine and adenine nucleotides are important endogenous modulators of neutrophil functions, and drugs may exert important actions via purinoceptors on neutrophil leukocytes.General Pharmacology 04/1997;