Besides the important role of emotional factors in the production of psychological-stress-induced analgesia (PSY-SIA), recent attention to the participation of serotonergic (5-HTnergic)neurons in the fear and anxiety-evoking mechanism led us to examine the effects of 5-HTnergic ligands on PSY-SIA. Pretreatment of mice with 2.0 to 10 mg/kg of methysergide, a 5-HT receptor antagonist, or 1.0 to 10 mg/kg of buspirone, a 5-HT_1A receptor partial agonist, dose-dependently suppressed the production of PSY-SIA. Ritanserin, a 5-HT₂ receptor antagonist, 1.0 to 5.0 mg/kg, or Y-25, 130, a 5-HT₃ receptor antagonist, 0.03 and 0.1 mg/kg, also inhibited PSY-SIA dose-dependently, while (±)pindolol, a 5-HT_1A/1B receptor antagonist, was ineffective at doses up to 3.0 mg/kg. Furthermore, the suppressive effect of PSY-stress on the development of antinociceptive tolerance to morphine was also antagonized by methysergide, buspirone, ritanserin and Y-25, 130, but not by (±)pindolol. These results suggest that 5-HT receptor (5-HT_1A, 5-HT₂ and 5-HT₃ but not 5-HT_1B)-mediated mechanisms play an important role in the production of PSY-SIA.