ABSTRACT
RFa-related peptides play a significant role in the processing of pain in the CNS of mammals. Recently it has been found that, when applied subcutaneously, these peptides elicit a powerful algogenic effect. The question arises whether this peripheral effect can be connected with the ability of RFa-related peptides to decrease the rate of desensitization of acid sensing ionic channels (ASICs) expressed in primary sensory neurons. We have addressed this question by comparing the effects of neuropeptide SF (NPSF), mammalian RFa peptide, in ASIC3-/- and wild-type C57BL/6J mice. Knockout of ASIC3 gene results in the changes in some of the behavioral parameters. However, subcutaneous injections of the NPSF into the n.saphenous innervation area result in a clearly nociceptive behavior in both strains of mice. There is no significant difference in the total time of licking of injected paw in the ASIC3-/- (194+/-22s) and C57BL/6J (227+/-25s) animals. Thus peripheral algogenic effects of NPSF cannot be explained only in terms of their action on the ASIC3 channels and involves some other, still unidentified mechanism.
Subject(s)
Neuropeptides/pharmacology , Nociceptors/physiology , Pain/metabolism , Sensory Receptor Cells/physiology , Sodium Channels/genetics , Acid Sensing Ion Channels , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Disease Models, Animal , Foot/innervation , Foot/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nociceptors/drug effects , Pain/chemically induced , Pain/genetics , Pain Measurement/drug effects , Pain Threshold/drug effects , Pain Threshold/physiology , Sensory Receptor Cells/drug effects , Species SpecificityABSTRACT
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.
