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.