Four hours after the acute administration of L-tryptophan (75 mg/kg) to either, nontolerant or morphine-tolerant mice, the antinociceptive effect of morphine was partially and significantly antagonized. Daily tryptophan administration to rats and mice during a 3-day morphine pellet implantation period increased the rates of both morphine tolerance development and development of physical dependence. The accelerating effect of tryptophan on tolerance and dependence development in mice was antagonized by pretreatment with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine. Acute tryptophan administration (75 mg/kg) significantly increased mouse brain 5-hydroxytryptamine levels for at least 4 hours. Although chronic tryptophan treatment increased 5-hydroxytryptamine turnover in morphine-treated mice, no effect of chronic morphine or tryptophan treatment on the particulate tryptophan hydroxylase activity of whole mouse brain was observed. Slight increases in tryptophan hydroxylase activity were observed in the caudate-putamen and septal areas of rat brain 3 and 6 days, respectively, after s.c. morphine pellet implantation. These and previous studies from our laboratory indicate that the development of morphine tolerance and dependence can be modified by agents affecting serotonergic mechanisms.