NEUROPEPTIDE FF, PAIN AND ANALGESIA

Neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) and the octadeca peptide neuropeptide AF r-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe- NH2) were isolated from bovine brain, and were initially characterized as anti-opioid peptides. They can oppose the acute effects of opioids and an increase in their brain concentrations may be responsible for the development of tolerance and dependence to opioids. Numerous exper iments suggest a possible neuromodulatory role for neuropeptide FF. A precursor protein has been identified, in particular in human brain. N europeptide FF immunoreactive neurons are present only in the medial h ypothalamus, and the nucleus of the solitary tract, and in the spinal cord in the superficial layers of the dorsal horn and areas around the central canal. Depolarization induces a Ca2+-dependent release of neu ropeptide FF immunoreactivity from the spinal cord. Neuropeptide FF ac ts through stimulation of its own receptors and high densities of spec ific binding sites are found in regions related either to sensory inpu t and visceral functions or to the processing of nociceptive messages. In both isolated dorsal root ganglion neurons and CAI pyramidal neuro ns of the hippocampus, neuropeptide FF has little effect of its own bu t reverses the effects of mu-opioid receptor agonists. In agreement wi th the hypothesized anti-opioid role of neuropeptide FF, supraspinal i njection lowers the nociceptive threshold and reverses morphine-induce d analgesia in rats. Furthermore, immunoneutralization of neuropeptide FF increases endogenous and exogenous opioid-induced analgesia. Simil arly, microinfusion of neuropeptide FF or neuropeptide FF analogs into the nucleus raphe dorsalis, the parafascicular nucleus, or the ventra l tegmental area has no effect on the nociceptive threshold but inhibi ts the analgesia induced by co-injected morphine. Furthermore, infusio n of neuropeptide FF into the parafascicular nucleus or the nucleus ra phe dorsalis reverses the analgesic effect of morphine infused into th e nucleus raphe dorsalis or the parafascicular nucleus, respectively, demonstrating remote interactions between neuropeptide FF and opioid s ystems. By contrast, intrathecal administration of neuropeptide FF ana logs induces a long lasting, opioid-dependent analgesia and potentiate s the analgesic effect of morphine. Analgesic effects of neuropeptide FF after supraspinal injection could also be observed, for example dur ing nighttime. In young mice, (1DMe)Y8Famide (D.Tyr-Leu(NMe)Phe-Gln-Pr o-Gln-Arg-Phe-NH2), a neuropeptide FF analog, increases delta-opioid r eceptor-mediated analgesia. These findings indicate that neuropeptide FF constitutes a neuromodulatory neuronal system interacting with opio id systems, and should be taken into account as a participant of the h omeostatic process controlling the transmission of nociceptive informa tion. (C) 1998 Elsevier Science B.V.