Tolerance and dependence to opiates may be an adaptive process that limits excessive effects of morphine on the CNS. Because no consistent opiate receptor reduction in chronically treated rats seems to underlie the hyposensitivity to morphine, an alternative hypothesis has postulated a role of "antiopioid" peptides. It is possible to speculate that the administration of morphine stimulates antiopioid systems such as neuropeptide FF (NPFF), as part of an homeostatic mechanism contributing to the development of tolerance. To test this hypothesis, pain sensitivity, opiate dependence, and CNS NPFF-IR levels were estimated at different times after implantation of morphine pellets (2 x 75 mg; NIDA). Three hours after morphine pellet treatment the analgesic effect was maximum and it decreased rapidly during the following 12 h. Naloxone-precipitated withdrawal syndrome was detected as soon as 3 h after morphine pellet implantation and was maximal after 24 h. NPFF-IR levels were measured in the spinal cord, brain stem, and hypothalamus. A significant decrease of NPFF-IR was observed 1 h after morphine pellet implantation (-25% to -45% depending on the structures) followed by a drastic increase of NPFF-IR levels (+60 to +140%) between 3 and 6 h. NPFF-IR levels rapidly returned to baseline after 24-36 h. It is suggested that the activity of these NPFF-IR neurones may increase gradually as a consequence of the continuous stimulation of opiate receptors and be part of an adaptive process that is able to counteract morphine effects and to induce dependence and tolerance to the analgesic effects of opiates.