An unbiased place preference conditioning procedure was used to determine whether the repeated administration of morphine results in sensitization to its conditioned rewarding effects. Rats received once daily injections of saline or morphine (5.0 mg/kg; i.p.) for 5 days in a room distinct from that where conditioning would occur. Place preference conditioning commenced 72 h later. A minimum of three drug conditioning sessions was necessary for the establishment of morphine-induced conditioned place preferences in saline-pretreated rats. The minimum dose producing this effect was 5.0 mg/kg. In animals pre-exposed to morphine, significant place preferences occurred after only two drug conditioning sessions and in response to doses of 3.0 mg/kg and greater. The augmented response to morphine was apparent when conditioning commenced 3, 10 or 21 days after the cessation of morphine pretreatment. It was not apparent when conditioning commenced 1 day after treatment cessation. An enhanced response to morphine was also observed in rats which had previously received either fentanyl (0.016 mg/kg/day) or nicotine (0.4 mg/kg/day) for 5 days. Animals which received morphine or fentanyl in combination with naloxone (0.5 mg/kg; s.c.) for 5 days failed to exhibit a conditioned response to morphine. When, however, naloxone was administered in combination with nicotine, significant morphine-induced place preferences were still seen. These data demonstrate that both sensitization and cross-sensitization develop to the conditioned rewarding effects of morphine. Furthermore, they indicate that the sensitization induced by morphine and fentanyl, but not nicotine, is opioid-receptor mediated.