Cristhine Schallenberger

Anti-nociceptive properties of the xanthine oxidase inhibitor allopurinol in mice: role of A1 adenosine receptors

Background and purpose:  Allopurinol is a potent inhibitor of the enzyme xanthine oxidase, used primarily in the treatment of hyperuricemia and gout. It is well known that purines exert multiple effects on pain transmission. We hypothesized that the inhibition of xanthine oxidase by allopurinol, thereby reducing purine degradation, could be a valid strategy to enhance purinergic activity. The aim of this study was to investigate the anti‐nociceptive profile of allopurinol on chemical and thermal pain models in mice.

The NMDA antagonist MK-801 induces hyperalgesia and increases CSF excitatory amino acids in rats: reversal by guanosine.

Excitatory amino acids (EAAs) and their receptors play a central role in the mechanisms underlying pain transmission. NMDA-receptor antagonists such as MK-801 produce antinociceptive effects against experimental models of chronic pain, but results in acute pain models are conflicting, perhaps due to increased glutamate availability induced by the NMDA-receptor antagonists. Since guanosine and riluzole have recently been shown to stimulate glutamate uptake, the aim of this study was to examine the effects of guanosine or riluzole on changes in nociceptive signaling induced by MK-801 in an acute pain model. Rats received an i.p. injection of vehicle, morphine, guanosine, riluzole or MK-801 or a combined treatment (vehicle, morphine, guanosine or riluzole+MK-801) and were evaluated in the tail flick test, or had a CSF sample drawn after 30 min. Riluzole, guanosine, and MK-801 (0.01 or 0.1 mg/kg) did not affect basal nociceptive responses or CSF EAAs levels. However, MK-801 (0.5 mg/kg) induced hyperalgesia and increased the CSF EAAs levels; both effects were prevented by guanosine, riluzole or morphine. Hyperalgesia was correlated with CSF aspartate and glutamate levels. This study provides additional evidence for the mechanism of action of MK-801, showing that MK-801 induces hyperalgesia with parallel increase in CSF EAAs levels.

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

Background and purpose:  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.

Guanosine Prevents Thermal Hyperalgesia in a Rat Model of Peripheral Mononeuropathy

UNLABELLED 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.

Spinal mechanisms of antinociceptive action caused by guanosine in mice

It is well known that adenine-based purines exert multiple effects on pain transmission. Recently, we have demonstrated that intracerebroventricular (i.c.v.) administered guanine-based purines are antinociceptive against chemical and thermal pain models in mice. The present study was designed to further investigate the antinociceptive effects of guanosine in mice. Animals received an intrathecal (i.t.) injection of vehicle (0.1 mN NaOH) or guanosine (10 to 400 nmol). Measurements of cerebrospinal fluid (CSF) purine levels and spinal cord glutamate uptake were performed. Guanosine produced dose-dependent antinociceptive effects against tail-flick, hot-plate, intraplantar (i.pl.) capsaicin, and i.pl. glutamate tests. Additionally, i.t. guanosine produced significant inhibition of the biting behavior induced by i.t. injection of glutamate (175 nmol/site), AMPA (135 pmol/site), kainate (110 pmol/site), trans-ACPD (50 nmol/site), and substance P (135 ng/site), with mean ID(50) values of 140 (103-190), 136 (100-185), 162 (133-196), 266 (153-461) and 28 (3-292) nmol, respectively. However, guanosine failed to affect the nociception induced by NMDA (450 pmol/site) and capsaicin (30 ng/site). Intrathecal administration of guanosine (200 nmol) induced an approximately 120-fold increase on CSF guanosine levels. Guanosine prevented the increase on spinal cord glutamate uptake induced by i.pl. capsaicin. This study provides new evidence on the mechanism of action of guanosine presenting antinociceptive effects at spinal sites. This effect seems to be at least partially associated with modulation of glutamatergic pathways by guanosine.

Mechanisms involved in the antinociception induced by spinal administration of inosine or guanine in mice

It is well known that adenine-based purines exert multiple effects on pain transmission. Recently, we have demonstrated that guanine-based purines may produce some antinociceptive effects against chemical and thermal pain in mice. The present study was designed to investigate the antinociceptive effects of intrathecal (i.t.) administration of inosine or guanine in mice. Additionally, investigation into the mechanisms of action of these purines, their general toxicity and measurements of CSF purine levels were performed. Animals received an i.t. injection of vehicle (30mN NaOH), inosine or guanine (up to 600nmol) and submitted to several pain models and behavioural paradigms. Guanine and inosine produced dose-dependent antinociceptive effects in the tail-flick, hot-plate, intraplantar (i.pl.) glutamate, i.pl. capsaicin and acetic acid pain models. Additionally, i.t. inosine inhibited the biting behaviour induced by spinal injection of capsaicin and i.t. guanine reduced the biting behaviour induced by spinal injection of glutamate or AMPA. Intrathecal administration of inosine (200nmol) induced an approximately 115-fold increase on CSF inosine levels. This study provides new evidence on the mechanism of action of extracellular guanine and inosine presenting antinociceptive effects following spinal administration. These effects seem to be related, at least partially, to the modulation of A1 adenosine receptors.

Anticonvulsant Effect of Alternanthera Brasiliana Extract On Pentylenetetrazole-induced Seizures in Rats

Epilepsy is a disorder that affects 1-2% of the population and a significant percentage of these patients do not respond to anticonvulsant drugs available in the market suggesting the need to investigate new pharmacological treatments. Numerous substances have been tested for potential anticonvulsant activity, but only a few generated anticonvulsant drugs. In this study, the potential anticonvulsant effect of Alternanthera brasiliana extract was investigated using an animal model of acute epilepsy induced by pentylenetetrazol (PTZ). The animals received injections of A. brasiliana extract (20, 100 or 500 mg/kg) or vehicle; 30 minutes later, they received an injection of PTZ, and were then observed for 30 minutes. Seizure latency and duration were recorded. The administration of 20 mg/kg of A. brasiliana extract had an anticonvulsant effect when compared with the control group. Thus, further studies using other seizure models as well as the investigation of isolated fractions of the extract are needed to elucidate the mechanisms of action of A. brasiliana.