ADENOSINE RECEPTOR AGONISTS ATTENUATE AND ADENOSINE RECEPTOR ANTAGONISTS EXACERBATE OPIATE WITHDRAWAL SIGNS

Previous studies have demonstrated a role for adenosine in mediating o piate effects. Adenosine receptors and their functions have been shown to be regulated by chronic opiate treatment. This study examines the role of adenosine receptors in the expression opiate withdrawal behavi ors. The effects of single doses of parenterally administered adenosin e receptor subtype-selective agonists and antagonists on opiate withdr awal signs in morphine-dependent mice were measured. Mice received sub cutaneous morphine pellet treatment for 72 h and then underwent naloxo ne-precipitated withdrawal after pretreatment with adenosinergic agent s. Adenosine agonists attenuated different opiate withdrawal signs. Th e A(1) agonist R-N-6(phenylisopropyl)adenosine (0, 0.01, 0.02 mg/kg, I P) significantly reduced wet dog shakes and withdrawal diarrhea, while the A(2a)-selective agonist 2-p-(2-carboxethyl) phenylethylamino-5'-N -ethylcarboxamidoadenosine or CGS 21680 (0, 0.01, 0.05 mg/kg, IF) sign ificantly inhibited teeth chattering and forepaw treads. Adenosine rec eptor antagonists enhanced different opiate withdrawal signs. The aden osine A(1) antagonist 1,3-dipropyl-8-cyclopentylxanthine (0, 1, 10 mg/ kg, IP) significantly increased weight loss and the A(2) antagonist, 3 ,7-dimethyl-1-propargylxanthine (0, 1 and 10 mg/kg, IP) enhanced wet d og shakes and withdrawal diarrhea. Treatment effects of adenosinergic agents were not due to nonspecific motor effects, as demonstrated by a ctivity monitoring studies. These results support a role for adenosine receptors in the expression of opiate withdrawal and suggest the pote ntial utility of adenosine agonists in its treatment.