The effects of cyclic nucleotides and theophylline were assessed in mice rendered tolerant to and physically dependent on morphine by the pellet implantation procedure. Tolerance was quantified by the increase in amount of morphine to produce analgesia and dependence by the decrease in amount of naloxone to precipitate withdrawal jumping. By these criteria, pretreatment with a single intravenous injection of cyclic 3′, 5′-adenosine monophosphate (cAMP) was found to enhance markedly tolerance and dependence development. Repeated injections of theophylline were also affective. Cycloheximide and beta-adrenergic blockers prevented the accelerating effect of cAMP and with more frequent administration also decreased the development of tolerance and dependence. It is concluded that cAMP may have a role in morphine tolerance and dependence development.