Previous research has shown that under certain conditions environmental cues associated with morphine administration induce drug-opposite conditioned effects that mimic symptoms of opiate withdrawal. R. V. McDonald and S. Siegel (see record 2004-10475-001) extend these observations by demonstrating that acute exposure to a low dose of morphine induces symptoms of opiate withdrawal in rats previously exposed to a high dose of morphine. They hypothesized that early drug onset cues, repeatedly paired with later, larger drug effects, mediate the paradoxical effect of the low drug dose on behavior. They also hypothesized that conditioned withdrawal symptoms induced by the early drug onset cues may mediate the "priming" effect of drugs on relapse and craving. The authors of this comment discuss the degree to which the literature supports this hypothesis.