The effects of drugs that modify adrenergic or tryptaminergic mechanisms were tested on the analgesic action of morphine in mice. Analgesia was assessed by the hot plate method and phenylquinonewrithing method. Reserpine antagonized the analgesic action of morphine in both tests, the maximal effects occurring 6–8 h after the administration of reserpine. p‐Chlorophenylalanine antagonized the analgesic action of morphine as assessed by the writhing method but not by the hot plate method. The analgesic action of morphine was not modified in either test by pretreatment with α‐methyl‐p‐tyrosine, propranolol, phentolamine or methysergide. These results suggest that the analgesic action of morphine, as measured in the writhing test, may be mediated by 5‐hydroxytryptamine but that other mechanisms may be involved in the hot plate test.

1. The effect of morphine on the histamine content of the mouse brain has been investigated. The changes in the brain histamine level have been related to morphine-induced analgesia and morphine-induced changes in locomotor activity. 2. With doses of morphine between 1 and 5 mg/kg there was a significant increase in histamine levels. The time required to produce a maximal rise in the brain histamine level with 5 mg/kg of morphine was 15 min. 3. There was a significant decrease in brain histamine levels with doses of morphine between 7-5 and 100 mg/kg. The time at which the greatest decrease was produced with 50 mg/kg was 30 min. 4. The time couse of the alteration of brain histamine by morphine did not correlate with its antinociceptive activity. Both the 5 and 50 mg/kg doses of morphine produced analgesia in mice whereas brain histamine levels were increased and decreased, respectively. 5. Pretreating mice with compounds which modify histaminergic function did not modify the antinociceptive action of morphine. 6. Morphine produced a biphasic effect on locomotor activity when the dose was increased from 0-5 through to 100 mg/kg. Doses up to 2-5 mg/kg caused a reduction of activity and doses above this produced significant increases. 7. There appears to be an inverse relationship between the morphine-induced changes of brain histamine and the morphine-induced changes in locomotor activity.