Adenosine receptors are involved in the control of acute naloxone-precipitated withdrawal: In vitro evidence

The effects exerted by adenosine A(1) and A(2) receptor agonists and antago nists on the acute opiate withdrawal induced by morphine were investigated in vitro. Following a 4 min in vitro exposure to morphine, the guinea-pig i solated ileum exhibited a strong contracture after the addition of naloxone . The P1 adenosine receptor agonist, adenosine, was able to reduce dose-dep endently naloxone-precipitaded withdrawal. The same effect was induced by t he adenosine A(1) receptor agonist, N-6-Cyclopentyladenosine (CPA) whereas the selective adenosine A(2A) receptor agonist CGS 21680 increased the nalo xone-precipitated withdrawal phenomenon. Dipyridamole, a blocker of adenosi ne reuptake, induced a significant reduction of morphine dependence. Caffei ne, an adenosine receptor antagonist, significantly increased the naloxone- precipitated withdrawal effect in a concentration dependent manner. The sam e effect was observed with 8-phenyltheophylline (8PT), an A(1) adenosine re ceptor antagonist, whereas 3,7-dimethyl-1-propargylxanthine (DMPX), an A(2) adenosine receptor antagonist, reduced the naloxone-precipitated withdrawa l phenomenon. The results of our experiments indicate that both A(1) and A(2) adenosine r eceptor agonists and antagonists are able to influence opiate withdrawal in vitro, suggesting an important functional interaction between the adenosin e receptors and opioid withdrawal.