RATIONALE: Indirect-acting serotonin (5-HT) receptor agonists can enhance the antinociceptive effects of morphine; however, the specific 5-HT receptor subtype(s) mediating this enhancement is not established. OBJECTIVE: This study examined interactions between morphine and both 5-HT(1A) and 5-HT(2A) receptor agonists in rats using measures of antinociception (radiant heat tail flick and warm water tail withdrawal), drug discrimination (3.2 mg/kg morphine versus saline), and locomotion. METHODS: Male Sprague-Dawley rats (n = 7-8 per group) were used to examine the effects of morphine alone and in combination with DOM (5-HT(2A) agonist) and 8-OH-DPAT (5-HT(1A) agonist). RESULTS: DOM did not modify antinociceptive or discriminative stimulus effects while modestly attenuating locomotor-stimulating effects of morphine; the effect of DOM (0.32 mg/kg) on morphine-induced locomotion was prevented by the 5-HT(2A) receptor-selective antagonist MDL 100907. In contrast, 8-OH-DPAT (0.032-0.32 mg/kg) fully attenuated the antinociceptive effects (both procedures), did not modify the discriminative stimulus effects, and enhanced (0.32 mg/kg) the locomotor-stimulating effects of morphine. These effects of 8-OH-DPAT were prevented by the 5-HT(1A) receptor-selective antagonist WAY100635. CONCLUSION: Agonists acting at 5-HT(1A) or 5-HT(2A) receptors do not modify all effects of mu opioid receptor agonists in a similar manner. Moreover, interactions between 5-HT and opioid receptor agonists vary significantly between rats and nonhuman primates, underscoring the value of comparing drug interactions across a broad range of conditions and in multiple species.