Adenosine kinase inhibitors attenuate opiate withdrawal via adenosine receptor activation

Previous studies have demonstrated a role for adenosine in mediating opiate effects. This study examines the effects of indirect activation of adenosi ne receptors, via treatment with adenosine kinase inhibitors, on the expres sion of opiate withdrawal in mice. Mice receive chronic morphine treatment via implantation of subcutaneous morphine pellets (75 mg) for 72 h. Mice th en receive parenteral treatment with adenosine kinase inhibitors, either 5' -amino-5'-deoxyadenosine (2, 5, 20, 40 mg/kg, intraperitoneal or i.p.) or i odotubericidin (1, 2, 5 mg/kg, i.p.), followed by naloxone injection and op iate withdrawal signs are measured over 20 min. Both adenosine kinase inhib itors significantly reduce the following opiate withdrawal signs in a dose- dependent manner compared to vehicle: withdrawal jumps, teeth chattering, f orepaw tremors, and forepaw treads. Additionally, 5'-amino-5'-deoxyadenosin e significantly reduces withdrawal-induced diarrhea and weight loss. Effect s of 5'-amino-5'-deoxyadenosine (40 mg/kg) on opiate withdrawal signs appea r to be mediated via adenosine receptor activation as they are reversed by pretreatment by adenosine receptor antagonist caffeine (20 mg, i.p.) but no t by selective phosphodiesterase inhibitor Po 20-1724 (10 mg/kg, i.p.). Ade nosine receptor activation via adenosine kinase inhibitor treatment attenua tes opiate withdrawal and these agents may be generally useful in the treat ment of drug withdrawal syndromes. (C) 1998 Elsevier Science B.V. All right s reserved.