Dual effects of Rho-kinase inhibitors on a rat model of inflammatory pain

BACKGROUND: Rho-kinases (ROCKs), a family of small GTP-dependent enzymes, are involved in a range of pain models, and their inhibition typically leads to antinociceptive effects

Redução do efeito analgésico da estimulação elétrica nervosa transcutânea de baixa freqüência em ratos tolerantes à morfina Reduction in analgesic effect from low-frequency transcutaneous electrical nerve stimulation in morphine-tolerant rats

OBJETIVO: Investigar o efeito da TENS de baixa (10 Hz) e alta freqüência(130 Hz) aplicadas na pata inflamada do rato após tratamento crônico com morfina. MÉTODO: Foram utilizados 140 ratos Holtzman fêmeas, nos quais a carragenina (Cg 250 µg/0,1ml) foi administrada na pata posterior direita para a indução da inflamação. TENS de baixa e alta freqüência foi aplicada por 20 min, após 2 h e 30 min da Cg e seu efeito medido através do método de Randall-Selitto. O antagonista opióide Naltrexona (3mg/kg,sc), foi administrado 30 minutos antes da TENS para verificar a liberação de substâncias opióides endógenas. A tolerância foi obtida após administração da morfina (10 mg/kg,sc), duas vezes ao dia, durante sete dias. O tratamento com TENS de baixa e alta freqüência foi realizado no oitavo dia às 2 h e 30 min após Cg. A análise estatística foi feita pelo método da análise de variância ANOVA (One Way) seguido de um teste "post hoc" (Teste de Bonferroni), com nível de significância quando p < 0,05. RESULTADOS: TENS de baixa e alta freqüência inibiu em 100% a hiperalgesia induzida pela Cg. Animais tratados previamente com naltrexona mostraram completa reversão da analgesia induzida pela baixa freqüência mas não pela alta freqüência. Após tolerância à morfina, os valores da TENS de baixa freqüência indicaram total ausência de analgesia, ao contrário da TENS de alta freqüência que induziu anti-hiperalgesia. CONCLUSÃO: Conclui-se que a atividade analgésica da TENS de baixa freqüência é reduzida após o desenvolvimento de tolerância a morfina.<br>OBJECTIVE: To investigate the effects of low (10 Hz) and high-frequency (130 Hz) transcutaneous electrical nerve stimulation (TENS) applied to inflamed paws of rats following chronic treatment with morphine. METHOD: 140 female Holtzman rats were utilized. Carrageenan (250 µg/0.1 ml) was administered to the right hind paws to induce inflammation. Two and a half hours after carrageenan injection, low and high frequency TENS was applied to the inflamed paw for 20 min, and its effect was measured via the Randall-Selitto method. The opioid antagonist naltrexone (3.0 mg/kg, subcutaneously) was administered 30 min before TENS, to verify the release of endogenous opioids. Morphine tolerance (10 mg/kg, subcutaneously) was induced by twice-daily injection over seven days. Low and high frequency TENS treatment was carried out on the eighth day, 2.5 hours after carrageenan injection. Statistical analysis was performed using one-way analysis of variance (ANOVA), followed by the post hoc Bonferroni test, with a significance level of p < 0.05. RESULTS: Both low and high frequency produced 100% inhibition of carrageenan-induced hyperalgesia. Naltrexone-treated animals showed complete reversion of analgesia induced by low but not high-frequency TENS. After attaining morphine tolerance, the low-frequency TENS values indicated complete absence of analgesia, whereas high-frequency TENS induced anti-hyperalgesia. CONCLUSION: The analgesic activity of low-frequency TENS is reduced following the development of morphine tolerance

Hyperalgesic effect induced by barbiturates, midazolam and ethanol: pharmacological evidence for GABA-A receptor involvement

The involvement of GABA-A receptors in the control of nociception was studied using the tail-flick test in rats. Non-hypnotic doses of the barbiturates phenobarbital (5-50 mg/kg), pentobarbital (17-33 mg/kg), and thiopental (7.5-30 mg/kg), of the benzodiazepine midazolam (10 mg/kg) or of ethanol (0.4-1.6 g/kg) administered by the systemic route reduced the latency for the tail-flick response, thus inducing a 'hyperalgesic' state in the animals. In contrast, non-convulsant doses of the GABA-A antagonist picrotoxin (0.12-1.0 mg/kg) administered systemically induced an increase in the latency for the tail-flick response, therefore characterizing an 'antinociceptive' state. Previous picrotoxin (0.12 mg/kg) treatment abolished the hyperalgesic state induced by effective doses of the barbiturates, midazolam or ethanol. Since phenobarbital, midazolam and ethanol reproduced the described hyperalgesic effect of GABA-A-specific agonists (muscimol, THIP), which is specifically antagonized by the GABA-A antagonist picrotoxin, our results suggest that GABA-A receptors are tonically involved in the modulation of nociception in the rat central nervous syste