In rats, morphine may either raise or lower body temperature depending on the dose. A morphine dose of 50 mg/kg, i.p., consistently produced a nearly maximal hypothermic response in non tolerant rats, whereas this dosage induced an elevation of body temperature in tolerant rats. In rats pretreated with alpha-fluoromethylhistidine (alpha-FMH), an irreversible inhibitor of histidine decarboxylase which induces a reduction in brain histamine synthesis, this morphine dose of 50 mg/kg, i.p. produced an elevation of rectal temperature resembling that observed in morphine-tolerant rats. To confirm the suggestion that hyperthermic effects of the higher dose of morphine in morphine-tolerant rats or in alpha-FMH-pretreated rats could be related to a possible involvement of mediators of fever, e.g. prostaglandins, animals were pretreated with acetylsalicylic acid (aspirin, Bayer) 30 mg/kg, i.p., 60 min before morphine. Results showed that acetylsalicylic acid prevented the hyperthermic response of morphine, resulting in a fall in body temperature. Since morphine releases histamine and alpha-FMH inhibits histamine synthesis, our data demonstrating that an inhibitor of prostaglandin-synthetase showed efficacy only in animals responding with fever to the higher dose of the opiate, suggests a physiological antagonism between histamine and prostaglandins on mechanisms underlying hyper/hypothermic responses to morphine.