Repetitive firing in axons can lead to their subexcitability and reduced conduction velocity, due to prolonged hyperpolarization (Gasser, 1935;Bergmans, 1970;Bostock & Grafe, 1985). Such activity-dependent changes in membrane potential and conduction velocity are much more pronounced in unmyelinated fibres than in myelinated ones (Ritchie & Straub, 1957;Grafe et al. 1997), and have been used in microneurographic recordings from humans as a 'marking' technique for C fibres activated by natural stimuli (Hallin &
3. Sixteen of the eighteen cold-specific units were also studied by electrical stimulation of their RFs. They conducted in the velocity range 0.8-3.0 m s _1. When stimulated at 2 Hz, their latency increased according to a characteristic time course, reaching a plateau within 3 min (mean slowing (± S.D.) 5.2 ± 1.1 %) and recovering quickly (50 % recovery in 17.8 ± 4.5 s).4. To reconcile these findings with previous studies of reaction times and the effects of nerve compression on sensation, it is concluded that either human cold-specific afferent fibres are incompletely myelinated 'BC' fibres, or else there are C as well as Ad cold fibres, with the C fibre group contributing little to sensation.
Velocity changes following single and double conditioning impulses were studied by microneurography in single human C fibres to provide information about axonal membrane properties. C units were identified as mechano‐responsive (n= 19) or mechano‐insensitive (12) nociceptors, cold‐sensitive (8) or sympathetic fibres (9), and excited by single, double and triple electrical stimuli to the skin at mean rates of 0.25–2 Hz. The interval between single or paired (20 ms apart) conditioning stimuli and test stimulus was then varied between 500 and 2 ms, and recovery curves of velocity change against inter‐spike interval constructed, allowing for changes in these variables with distance. All fibres exhibited an initial (4–24 ms) relative refractory phase, and a long‐lasting (>500 ms) ‘H2’ phase of reduced velocity, attributed to activation of Na+/K+‐ATPase. Mechano‐responsive nociceptors exhibited an intermediate phase of either supernormality or subnormality, depending on stimulation rate. Mechano‐insensitive nociceptors behaved similarly, but all were supernormal at 1 Hz. Sympathetic units exhibited only a long‐lasting supernormality, while cold fibres exhibited a briefer supernormal and a late subnormal phase (H1), similar to A fibres. A pre‐conditioning impulse doubled H2 and increased H1, but did not augment supernormality or the subnormality of similar time course. Like A fibre supernormality, these phenomena were explained by a passive cable model, so that they provide an estimate of membrane time constant. Nociceptor membrane time constants (median 110 ms, n= 17) were rather insensitive to membrane potential, indicating few active voltage‐dependent potassium channels, whereas sympathetic time constants were longer and reduced by activity‐dependent hyperpolarisation.
Differential A-fibre block of human peripheral nerves changes the sensation evoked by innocuous cooling (∼24• C) of the skin from 'cold' to 'hot' or 'burning', and this has been attributed to activity in unidentified unmyelinated fibres that is normally masked or inhibited by activity in Aδ cold fibres. Application of the TRPM8 agonist menthol to the skin evokes 'burning/stinging' as well as 'cold', and the unpleasant sensations are also enhanced by A-fibre block. In this study we used microneurography to search for C fibres in human skin activated by cooling and menthol, which could be responsible for these phenomena. Afferent C fibres were classified by activity-dependent slowing as Type 1A (polymodal nociceptor), Type 1B (mechanically insensitive nociceptor) or Type 2 (cold sensitive), and their responses to heating and cooling ramps were measured before and after topical application of menthol preparations (2-50%). The only C fibres activated by menthol were the Type 2 fibres, which discharged vigorously with innocuous cooling and were strongly activated and sensitized to cooling by menthol. Unlike an Aδ cold fibre, they continued to discharge at skin temperatures down to 0• C, and most (13/15) were also activated by heating. We propose that the Type 2 C fibres, although resembling Aδ cold fibres in their responses to innocuous cooling and menthol, have a more complex sensory function, colouring with a 'hot-burning' quality the perceptions of low and high temperatures. Their bimodal thermoreceptive properties may help account for several puzzling psychophysical phenomena, such as 'innocuous cold nociception', 'paradoxical heat' and the thermal grill illusion, and also for some neuropathic pains.
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