Neuropeptide FF and FMRFamide Potentiate Acid-Evoked Currents from Sensory Neurons and Proton-Gated DEG/ENaC Channels FF is injected intracerebroventricularly, it elicits hyperal-gesia and a reduction in morphine-induced analgesia (Tang et allike immunoreactive ma

  • Askwith C
  • Cheng C
  • Ikuma M
  • et al.
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Medicine terial is released in mammals following chronic mor-‡ Department of Physiology and Biophysics phine administration, and anti-FMRFamide antibodies University of Iowa College of Medicine can enhance morphine's effects (Tang et al., 1984; De-Iowa City, Iowa 52242 villers et al., 1995). However, when administered intra-thecally, these peptides can have an analgesic effect thought to be mediated through opioid receptors (Raffa, Summary 1988; Raffa and Connelly, 1992; Gouardé res et al., 1993; Roumy and Zajac, 1998). Acidosis is associated with inflammation and ischemia Some effects of FMRFamide and neuropeptide FF and activates cation channels in sensory neurons. In-appear to be mediated through opioid receptors; these flammation also induces expression of FMRFamide-effects are blocked by the opioid antagonist naloxone like neuropeptides, which modulate pain. We found (Kavaliers and Hirst, 1985; Kavaliers, 1987; Raffa, 1988; that neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Gouardé res et al., 1993; Roumy and Zajac, 1998). Yet, Phe amide) and FMRFamide (Phe-Met-Arg-Phe amide) other effects of FMRFamide and FMRFamide-related generated no current on their own but potentiated peptides are independent of opioid receptors and are H-gated currents from cultured sensory neurons and insensitive to naloxone (Gayton, 1982; Raffa et al., 1986; heterologously expressed ASIC and DRASIC channels. Kavaliers, 1987; Raffa, 1988; Allard et al., 1989; Roumy The neuropeptides slowed inactivation and induced and Zajac, 1998). In mammals, the nonopioid receptor(s) sustained currents during acidification. The effects for FMRFamide and related peptides has not been iden-were specific; different channels showed distinct re-tified, and it is not known how these peptides modulate sponses to the various peptides. These results sug-pain sensation. However, the discovery of a FMRFamide-gest that acid-sensing ion channels may integrate activated Na channel (FaNaCh) in the mollusc Helix multiple extracellular signals to modify sensory per-aspersa (Lingueglia et al., 1995) provided a clue that ception. similar receptors might exist in mammals. Unlike many neuropeptide receptors, FaNaCh is an ion Introduction channel gated directly by its peptide ligand, FMRFamide (Lingueglia et al., 1995). The neuropeptide receptor FMRFamide (Phe-Met-Arg-Phe amide) and related pep-FaNaCh is a member of the DEG/ENaC family of chan-tides comprise a family of neuropeptides that are abun-nels. DEG/ENaC channels are homo-or heteromultimers dant in many invertebrates, including Caenorhabditis composed of multiple subunits (Bassilana et al., 1997; elegans (Nelson et al., 1998), Aplysia californica (Green-Lingueglia et al., 1997; Coscoy et al., 1998; Waldmann berg and Price, 1992), and Drosophila melanogaster and Lazdunski, 1998). Each subunit contains two trans-(Schneider and Taghert, 1988). In these organisms, membrane domains separated by a large, extracellular, FMRFamide-like neuropeptides act as neurotransmit-cysteine-rich domain and cytosolic N and C termini (Wald-ters and neuromodulators. At least one gene encoding mann and Lazdunski, 1998). DEG/ENaC channels are FMRFamide-related peptides is present in mammals; it not voltage gated and are cation selective (usually Na produces neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-K). FaNaCh is the only known DEG/ENaC channel that Arg-Phe amide) and neuropeptide AF (A18Famide) (Perry acts as a neuropeptide receptor. Other members of this et al., 1997; Vilim et al., 1999). Although FMRFamide family are involved in mechanosensation, salt taste, and itself has not been discovered in mammals (Yang et al., epithelial Na absorption (Schild et al., 1995; Snyder et 1985), administration of FMRFamide induces a variety al., 1995; Lindemann, 1996; Mano and Driscoll, 1999). of physiologic effects, including alterations in blood Although a mammalian FaNaCh has not yet been iso-pressure, respiratory rate, glucose-stimulated insulin related , mammals do possess multiple DEG/ENaC family lease, and behavior (Mues et al., 1982; Sorenson et al., members. Interestingly, one subset of this channel fam-1984; Kavaliers and Hirst, 1985; Raffa et al., 1986; Kava-ily, the acid-sensing ion channels, has been postulated liers, 1987; Telegdy and Bolló k, 1987; Thiemermann et to play a role in sensory perception and may, like al., 1991; Muthal et al., 1997; Nishimura et al., 2000). In FMRFamide, play a role in pain perception (Waldmann mammals, FMRFamide and neuropeptide FF also mod-and Lazdunski, 1998). The acid-sensing DEG/ENaC ify the response to painful stimuli, and neuropeptide FF channels respond to protons and generate a voltage-is induced by inflammation (Tang et al., 1984; Yang et insensitive cation current when the extracellular solution al., 1985; Raffa and Connelly, 1992; Kontinen et al., 1997; is acidified. Vilim et al., 1999). When FMRFamide or neuropeptide The tissue acidosis associated with inflammation, infection , and ischemia causes pain (Reeh and Steen, 1996). Acidosis also generates proton-dependent tran-§ To whom correspondence should be addressed (e-mail: mjwelsh@ sient and sustained Na currents in cultured sensory




Askwith, C. C., Cheng, C., Ikuma, M., Benson, C., Price, M. P., & Welsh, M. J. (2000). Neuropeptide FF and FMRFamide Potentiate Acid-Evoked Currents from Sensory Neurons and Proton-Gated DEG/ENaC Channels FF is injected intracerebroventricularly, it elicits hyperal-gesia and a reduction in morphine-induced analgesia (Tang et allike immunoreactive ma. Kavaliers (Vol. 26, pp. 133–141). Roumy and Zajac. Retrieved from

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