Administration of the serotonin (5-HT) releasing compound p-chloroamphetamine (PCA; 2.5 mg/kg) induced potent analgesia in rats tested with the hot plate method. The analgesia was prevented by pretreatment with either of the 5-HT uptake inhibitors alaproclate (20 mg/kg) or fluoxetine (10 mg/kg). Taking into account that the noradrenergic uptake inhibitor desipramine in previous experiments failed to interfere with the effect of PCA, these results demonstrate that PCA selectively acts on 5-HT terminals. The analgesia was attenuated by administration of the 5-HT antagonists methiothepin (0.125-0.5 mg/kg) and danitracen (0.25-2.5 mg/kg) but not by a series of other 5-HT receptor antagonists or antagonists acting on noradrenergic, dopaminergic, GABAergic, histaminergic or muscarinic receptors. It is concluded that the analgesic effect of PCA is mediated via stimulation of a type of 5-HT receptors possibly belonging to the 5-HT-1 class. Further studies are, however, needed in order to firmly establish the relationship to any particular sub-type of 5-HT receptor as characterized in in vitro binding studies.