Neuropeptide FF receptors control morphine-induced analgesia in the parafascicular nucleus and the dorsal raphe nucleus.

The ability of (1DMe)Y8Fa (D.Tyr-Leu-(NMe)Phe-Gln-Pro-Gln-Arg-Phe-NH2), a selective neuropeptide FF analog resistant to enzymatic degradation, to control morphine-induced analgesia was investigated in rat after microinfusion into the dorsal raphe nucleus and the nucleus parafascicularis of the thalamus. Infusion of (1DMe)Y8Fa (2.5 nmol) in the nucleus raphe dorsalis did not modify the animal response in the tail-immersion test but significantly reversed analgesia induced by coinjected morphine (27 nmol). Similarly, (1DMe)Y8Fa (5 nmol) inhibited morphine effects in the hot-plate test after co-injection into the parafascicular nucleus. Furthermore, (1DMe)Y8Fa injected into the parafascicular nucleus attenuated analgesia induced by morphine injected into the nucleus raphe dorsalis and similarly, the neuropeptide FF analog in the nucleus raphe dorsalis decreased the effects of 27 nmol morphine injected in the parafascicular nucleus. The density of neuropeptide FF receptors did not decrease in the nucleus raphe dorsalis after lesion of serotonergic neurons by 5,7-dihydroxytryptamine. However, after this lesion, (1DMe)Y8Fa injected in the nucleus raphe dorsalis was no longer able to modify analgesic effects of morphine in hot-plate and tail-immersion tests. Similarly, the serotonin (5-HT) depletion induced by a systemic administration of para-chlorophenylalanine did not modify morphine analgesia microinjected into the nucleus raphe dorsalis and the parafascicular nucleus but blocked the ability of (1DMe)Y8Fa to reverse morphine effects in both nuclei. These data show that neuropeptide FF exerts anti-opioid effects directly into both the nucleus raphe dorsalis and the parafascicular nucleus and acts also at distance on opioid functions. Furthermore, anti-opioid effects of neuropeptide FF require functional serotonergic neurons although neuropeptide FF receptors are not carried on these neurons.