Effect of a selective GABA_B receptor agonist baclofen on the μ-opioid receptor agonist-induced antinociceptive, emetic and rewarding effects

The management of excessive adverse effects of opioids is a major clinical problem. The present study was undertaken to investigate the effect of a selective γ-aminobutyric acid (GABA)_B receptor agonist baclofen on the μ-opioid receptor agonist-induced antinociceptive, emetic and rewarding effects. Either morphine or fentanyl produced a dose-dependent antinociceptive effect in both ferrets using Randall-Selitto test and mice using tail-flick test. Under these conditions, pretreatment of baclofen produced an additive antinociception induced by morphine or fentanyl. Furthermore, the augmentation of antinociception induced by systemic administration of baclofen with morphine or fentanyl was completely abolished by either i.c.v. or i.t. pretreatment with the selective GABA_B receptor antagonist CGP 35348 in mice. We next investigated the emetic response induced by μ-opioid receptor agonist in ferrets. Morphine at lower doses than that used for antinociceptive assay produced both retching and vomiting, whereas fentanyl failed to produce the retching and vomiting in ferrets. Here we reported for the first time that baclofen significantly suppressed the retching and vomiting induced by morphine, indicating the involvement of GABA_B receptor in emetic control pathway. Furthermore, baclofen also inhibited place preference elicited morphine or fentanyl in rats. Taken together, these results suggest that co-administration of baclofen with μ-opioid receptor agonist produced a potentiation of antinociceptive effect, whereas an untoward effect was completely blocked.