Cable F ault M onitoring a nd I ndication : A Review

Abstract

Introduction and Purpose: Opioids are effective analgesic agents but serious adverse effects such as; tolerance and withdrawal contribute to opioid dependence and limit their use. Opioid withdrawal is a common occurrence in human opiate addicts that is no life threatening. Studies have shown that the mesocorticolimbic system, especially nucleus accumbens is an important region in drug addiction and adenosine A1 and A2A receptors play a modulatory role in the mechanism of action of drug dependece and withdrawal. The aim of this study was to investigate the effects of selective A1 agonist CPA and selective A2A antagonist SCH58261 on locomotor activity behavior, withdrawal symptoms and concentration of dopamine and noradrenaline in the nucleus accumbens, during naloxone precipitated withdrawal in morphine dependent rats. Methods: Experiments were carried out with male Sprague Dawley animals, aged 4-6 months. All the experimental procedures were approved by the local ethical committee MUHDEK (55.2012.mar) and financed by BAPKO (Scientific Research Projects Unit of Marmara University). Selective A1 agonist CPA (0.5; 1.0; 2.0 mg/ml) and selective A2A antagonist SCH58261 (0.35; 0.70; 1.40 mg/ml) was dissolved in dimethylsulfoxide and given to the nucleus accumbens core through the implanted guide cannulas. Rats were made dependent by implantation of 3 morphine pellets s.c. (75 mg morphine base). Withdrawal was evaluated by injection of the opioid antagonist, naloxone (2 mg/kg, i.p.). Withdrawal symptoms and locomotor activity behavior during naloxone induced opioid withdrawal were examined. Rats were decapitated immediately after examination of locomotor activity behavior and the brains were stored at -40degreeC until use. After dissection of nucleus accumbens, tissue punches were homogenized for determination dopamine and noradrenaline by highperformance liquid chromatography (HPLC). All homogenate samples were stored frozen at -80degreeC until use. Summary: Local CPA (1.0 mg/ml) administration in nondependent rats decreased all parameters of locomotor activity (p<0.05 - p<0.01) and increased concentrations of dopamine (p<0.01) and noradrenaline (p<0.05) in the nucleus accumbens. Local CPA (0.5 mg/ml and 1.0 mg/ml) administration decreased Gellert-Holtzman withdrawal scale (p<0.05) and weight loss (p<0.05), increased concentrations of dopamine (p<0.05, p<0.01) and noradrenaline (p<0.01) in the nucleus accumbens during naloxone induced withdrawal. Local SCH58261 (0.35 mg/ml and 0.70 mg/ml) administration decreased Gellert- Holtzman withdrawal scale (p<0.01) during naloxone induced withdrawal. Local administration of SCH58261 0.70 mg/ml increased concentrations of dopamine (p<0.01) and noradrenaline (p<0.05), local administration of SCH58261 1.40 mg/ml increased concentrations of noradrenaline (p<0.05) during naloxone induced withdrawal. Conclusions: Our findings suggest that administration of adenosine A1 agonist and A2A antagonist significantly decreased withdrawal behaviors and increased dopamine and noradrenaline levels in opioid withdrawal in a dose-dependent manner. Weight loss was also reversed by A1 agonist during naloxone induced withdrawal. This results demonstrate that adenosine receptors should be examined as a potential mechanism that can be exploited for the treatment of morphine withdrawal.