RFamide (RFa)-related
peptides modulate
pain processing in the mammalian CNS. The effects of these
peptides are generally considered as 'anti-
opioid'. They also decrease the rate of desensitization of
acid-sensing
ionic channels (ASICs), putative nociceptors in dorsal root ganglia neurons [C. Askwith et al. (2000) Neuron, 26, 133-141]. We have tested the role of mollusc-derived
peptide, FMRFa (
Phe-Met-Arg-Phe-amide) and its synthetic analogues in peripheral nociception. Here we demonstrate that RFa-related
peptides powerfully excite the majority of C-fibres in the skin-nerve preparation of rat: 76% of 55 tested fibres with the conduction velocity below 2 m/s responded with long-lasting discharges to the application of
peptides (20 microm). When injected subcutaneously in vivo (mice), they initiate nociceptive behaviour. We confirm the data on humans [S. Ugawa et al. (2002) J. Clin. Invest., 110, 1185-1190]: the activation of C-fibres by
acid is inhibited by channel blocker of ASICs,
amiloride. However, there is no correlation in the sensitivity of C-fibres to RFa
peptides,
protons and
amiloride: 74% of tested RFa-sensitive C-fibres were insensitive to
protons and in 67% of cases the response to
peptides was insensitive to
amiloride. Thus, powerful excitatory/algogenic action of RFa-related
peptides cannot be interpreted solely in terms of their interaction with ASICs. The
peptides do not activate any conductance in the somatic membrane of dorsal root ganglion neurons of rats and probably affect still unidentified molecular target(s) responsible for nociceptive signalling.