Modulatory role of neuropeptide FF system in nociception and opiate analgesia

Abstract

The tetra-peptide FMRF-NH 2 is a cardioexcitatory peptide in the clam. Using the antibody against this peptide, FMRF-NH 2 -like immunoreactive material was detected in mammalian CNS. Subsequently, mammalian FMRF-NH 2 immunoreactive peptides were isolated from bovine brain and characterized to be FLFQPQRF-NH 2 (NPFF) and AGEGLSSPFWSLAAPQRF-NH 2 (NPAF). The genes encoding NPFF precursor proteins and NPFF receptors 1 and 2 are expressed in all vertebrate species examined to date and are highly conserved. Among many biological roles suggested for the NPFF system, the possible modulatory role of NPFF in nocicetion and opiate analgesia has been most widely investigated. Pharmacologically, NPFF-related peptides were found to exhibit analgesia and also potentiate the analgesic activity of opiates when administered intrathecally but attenuate the opiate induced analgesia when administered intracerebroventricularly. RF-NH 2 peptides including NPFF-related peptides were found to delay the rate of acid sensing ion channels (ASIC) desensitization resulting in enhancing acid gated currents, raising the possibility that NPFF also may have a pain modulatory role through ASIC. The genes for NPFF as well as NPFF-R2, preferred receptor for NPFF, are highly unevenly expressed in the rat CNS with the highest levels localized to the superficial layers of the dorsal spinal cord. These two genes are also present in the dorsal root ganglia (DRG), though at low levels in normal rats. NPFF and NPFF-R2 mRNAs were found to be coordinately up-regulated in spinal cord and DRG of rats with peripheral inflammation. In addition, NPFF-R2 immunoreactivity in the primary afferents was increased by peripheral inflammation. The findings from the early studies on the analgesic and morphine modulating activities suggested a role for NPFF in pain modulation and this possibility is further supported by the distribution of NPFF and its receptor and the regulation of the NPFF system in vivo. Published by Elsevier Ltd.

Endogenous Arginine-Phenylalanine-Amide-related Peptides Alter Steady-state Desensitization of ASIC1a

“…Both NPFF and ASIC1a are localized to the dorsal horn (33,57,58). In addition, NPFF and ASIC1a levels increase following inflammation (58,59). NPFF is known to limit ASIC1a desensitization following activation, an action that would potentiate ASIC1a activity (24).…”

ENaCs and ASICs as therapeutic targets

“…The finding that PcTx1 and ASIC1 antisense oligo-deoxynucleotides infused into the intrathecal space both had analgesic effects further suggests a role for ASIC1 in the central mediation of pain (108,272). Moreover, recently defined interactions between ASICs and peptides found within the CNS, such as the dynorphins, reinforce the possibility that CNS ASICs may be manipulated to manage pain (347,426).…”

GRK2 Protein-mediated Transphosphorylation Contributes to Loss of Function of μ-Opioid Receptors Induced by Neuropeptide FF (NPFF2) Receptors

“…Injection of NPFF analogs in rodents has been shown to modulate both analgesic (12)(13)(14) and motivational properties of opioid drugs (15,16). The NPFF system is therefore considered to be an opioid-modulating system involved in homeostasis that counteracts the action of opioids (17,18) and thus an interesting therapeutic target for the management of opiate tolerance and dependence (7).…”