CHANGES IN CNS NEUROPEPTIDE FF-LIKE MATERIAL, PAIN SENSITIVITY, AND OPIATE DEPENDENCE FOLLOWING CHRONIC MORPHINE TREATMENT

Tolerance and dependence to opiates may be an adaptive process that li mits excessive effects of morphine on the CNS. Because no consistent o piate receptor reduction in chronically treated rats seems to underlie the hyposensitivity to morphine, an alternative hypothesis has postul ated a role of ''antiopioid'' peptides. It is possible to speculate th at the administration of morphine stimulates antiopioid systems such a s neuropeptide FF (NPFF), as part of an homeostatic mechanism contribu ting to the development of tolerance. To test this hypothesis, pain se nsitivity, opiate dependence, and CNS NPFF-IR levels were estimated at different times after implantation of morphine pellets (2 x 75 mg; NI DA). Three hours after morphine pellet treatment the analgesic effect was maximum and it decreased rapidly during the following 12 h. Naloxo ne-precipitated withdrawal syndrome was detected as soon as 3 h after morphine pellet implantation and was maximal after 24 h. NPFF-IR level s were measured in the spinal cord, brain stem, and hypothalamus. A si gnificant decrease of NPFF-IR was observed 1 h after morphine pellet i mplantation (-25% to -45% depending on the structures) followed by a d rastic increase of NPFF-IR levels (+60 to +140%) between 3 and 6 h. NP FF-IR levels rapidly returned to baseline after 24-36 h. It is suggest ed 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 ef fects and to induce dependence and tolerance to the analgesic effects of opiates.