Differential influence of D₁ and D₂ dopamine receptors on acute opiate withdrawal in guinea-pig isolated ileum

Abstract

1. The effects exerted by D₁ and D₂ dopamine agonists and antagonists on the acute opiate withdrawal induced by μ- and κ-receptor agonists were investigated in vitro.

2. Following a 4 min in vitro exposure to morphine (moderately selective μ-agonist), [D-Ala², Me-Phe⁴, Gly-ol⁵]enkephalin (DAMGO, highly selective μ-agonist) or U-50488H (highly selective κ-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 μ- (morphine and DAMGO) and κ- (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 D₂ dopamine receptor antagonist, sulpiride, was also able to reduce dose-dependently both μ- and κ-opioid withdrawal, whereas the D₁-receptor selective antagonist SCH 23390 did not affect either μ- or κ-opioid withdrawal.

5. Bromocriptine, a D₂ selective dopamine receptor agonist was able to increase significantly, and in a concentration-dependent manner, the naloxone-induced contracture by μ- and κ-opioid agonists, whereas SKF 38393, a D₁ selective dopamine receptor agonist, increased only the withdrawal after morphine or U50-488H.

6. Our data indicate that both D₁ and D₂ 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 μ- and κ-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 D₂ dopamine receptors may be primarily involved in the control of opiate withdrawal.

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