Differential influence of D-1 and D-2 dopamine receptors on acute opiate withdrawal in guinea-pig isolated ileum

1 The effects exerted by D-1 and D-2 dopamine agonists and antagonists on the acute opiate withdrawal induced by mu- and kappa-receptor agonists were investigated in vitro. 2 Following a 4 min in vitro exposure to morphine (moderately selective mu-agonist), [D-Ala(2), Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO, highly selective mu-agonist) or U-50488H (highly selective kappa-agonist) the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. 3 The non-selective dopamine receptor antagonist haloperidol when added before or after the opioid agonists, was able dose-dependently to prevent or to reverse the naloxone-induced contracture after exposure to mu- (morphine and DAMGO) and kappa- (U-50488H) opioid agonists. The non-selective dopamine receptor agonist, apomorphine, was able to exert the same effects only at the highest concentration used. 4 The selective D-2 dopamine receptor antagonist, sulpiride, was also able to reduce dose-dependently both mu- and kappa-opioid withdrawal, whereas the D-1-receptor selective antagonist SCH 23390 did not affect either mu- or kappa-opioid withdrawal. 5 Bromocriptine, a D-2 selective dopamine receptor agonist was able to increase significantly, and in a concentration-dependent manner, the naloxone-induced contracture by mu- and kappa-opioid agonists, whereas SKF 38393, a D-1 selective dopamine receptor agonist, increased only the withdrawal after morphine or U50-488H. 6 Our data indicate that both D-1 and D-2 dopamine agonists and antagonists are able to influence opiate withdrawal in vitro, suggesting an important functional interaction between the dopaminergic system and opioid withdrawal at both the mu- and kappa-receptor level. 7 Furthermore, the ability of sulpiride to block strongly opiate withdrawal when compared to SCH 23390, as well as the effect of bromocriptine to increase opiate withdrawal suggest that D-2 dopamine receptors may be primarily involved in the control of opiate withdrawal.