C-fiber nociceptors not only serve afferent but also local efferent functions. The local efferent functions, such as vasodilatation, axon reflex flare reaction, plasma extravasation, and modulation of neuronal activity, are mediated via a local release of substance P, neurokinin A, and calcitonin gene-related peptide (CGRP) from the peripheral ending. CGRP is the main mediator of the capsaicin-induced flare reaction in the mammalian skin (including humans). In the pig skin the vasodilatation is due to activation of specific heat nociceptors. In the pigeon, antidromic vasodilatation is markedly inhibited by intrinsic galanin. Plasma extravasation in the pig skin blister base or using microdialysis can be evoked by histamine, but not by electrical stimulation or capsaicin. The neurogenic component of the histamine response (64%) appears to be mediated via NK2 receptors and can be modulated by CGRP. There is some evidence that the neuropeptides can also sensitize or stimulate nociceptors. Since in the fibromyalgia syndrome an increased sensitivity of the flare reaction has been observed, the hyperalgesia might be partly due to altered functions of C-fiber nociceptors.

The voltage clamp technique was used to study the effects of dendrotoxin (DTX) on outward potassium currents in internally perfused dorsal root ganglion neurones of guinea-pig. Sodium currents were eliminated by tetrodotoxin (TTX, 2 mumol/l), calcium currents and calcium-activated potassium conductances were abolished by intracellular perfusion of cells with KF. Depolarizing voltage shifts from a holding potential of -90 mV yielded a fast transient outward current (IfK) and a delayed non-inactivating outward current (IsK). These currents could be separated by shifting the membrane potential to -50 mV, where IfK was almost completely inactivated. DTX, at concentrations of 0.14-1.4 nmol/l selectively reduced a portion of the non-inactivating potassium current, leaving the transient outward current unaffected. Once manifested, the action of DTX could not be reversed by washing. The I-V characteristic of the current blocked by DTX is almost linear and quite different from the one of the 'DTX-resistant' portion of IsK, which shows a non-linear I-V curve. Tetraethylammonium (TEA, 30 mmol/l) strongly reduced IfK and IsK. However, subsequent application of DTX was still able to further reduce IsK. 3,4-diaminopyridine (3,4-DAP, 500 mumol/l) unselectively reduced IfK and a portion of IsK. The remainder of the latter could not further be reduced by DTX, suggesting a similar action of the two blockers on non-inactivating potassium currents. From the results presented, it is suggested that dendrotoxin selectively blocks a non-inactivating subtype of potassium channel.

The afferent properties of nerve fibres innervating the hairy skin of the pig hind limb were investigated by recording from 142 single units from the saphenous nerve. Identified single units were isolated using maximal electrical stimulation of the nerve trunk. Afferent units were classified on the basis of their responses to a range of stimuli, both thermal (heating to 60 degrees C and cooling to 10 degrees C) and mechanical (air jet, von Frey type filaments with forces of 0.1-250 mN, and strong pressure with a blunt needle). A-fibre units (conduction velocity 6.3-64 m/s, n = 60) fell into categories that have been described in hairy skin in other mammalian species. Most were mechanoreceptors, although seven typical A-fibre mechanical nociceptors with large, multipoint fields were also isolated. No cutaneous receptive field could be found for 15% of A-fibre units. Out of 62 C-fibre units (conduction velocity 0.49-2 m/s) 40% had no cutaneous field for pressure, heat or cold. Of the C-fibre units with cutaneous fields, 42% were polymodal nociceptors, 38% were mechanoreceptors with a variety of properties, including some excited by noxious heat, and 19% were heat-only nociceptors. C-polymodal nociceptors had large receptive fields up to 12.5 mm across and did not sensitize following strong heating. Twenty units conducted at 2-6.3 m/s, between the main C- and A-fibre bands, and were varied in their responses. Some had properties identical to C-fibre mechanoreceptors whilst four were sensitive cold thermoreceptors and one was a polymodal nociceptor. Two units were mechanical nociceptors with small receptive fields.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Skin blood flow has been imaged during stimulation of fine nerve filaments containing small numbers of identified C fibre units. Filaments were dissected from the saphenous nerve of anaesthetized pigs. 2. Stimulation of filaments containing C heat nociceptor units gave small areas of elevated blood flow (average increase 96 %, n = 11) restricted to the afferent receptive field. The extent of the areas of raised blood flow was imaged completely for 8 units. The average extent of vasodilatation in the direction of greatest spread was 8 mm and the maximum spread in any unit was 13 mm. 3. Stimulation of C polymodal nociceptor units never caused increases in blood flow7 in or near their receptive fields. 4. Localized noxious stimuli (55°C or intradermal injection of capsaicin) caused flare extending 7-15 mm in the same skin region. 5. In agreement with the axon reflex model, spread of flare was restricted to the zone innervated by the terminals of single C fibre units. 6. It is concluded that the C heat nociceptor units are the major class of afferent involved in the flare reaction in the skin of the pig. C polymodal nociceptor units do not appear to be involved in flare in this species. The probable situation in human skin, which is also innervated by heat nociceptors, is discussed.

The effect of capsaicin on voltage-dependent membrane currents of isolated dorsal root ganglia (DRG) neurones of guinea-pig and chicken were investigated by the voltage-clamp technique and intracellular perfusion. In both species, administration of capsaicin (3 X 10(-5) M) to the outer surface of the cell membrane reduced the amplitude and accelerated the inactivation of the fast inactivating potassium current. In contrast, 3,4-diaminopyridine (3,4-DAP) reduced the fast potassium current without affecting the inactivation. Combined application of capsaicin and 3,4-DAP was more effective than either drug alone. The slow potassium current was diminished by capsaicin but not affected by 3,4-DAP. Capsaicin (3 X 10(-5) M) applied to the internal surface of the membrane had little effect on the fast outward current but primarily decreased the amplitude of the slow potassium current. Two subpopulations of sodium currents could be demonstrated in guinea-pig neurones according to their tetrodotoxin (TTX) sensitivity. In type I neurones the sodium current was completely blocked by TTX; type II neurones exhibited a TTX-sensitive as well as a TTX-resistant inward current. Capsaicin (3 X 10(-5) M) applied externally reduced the maximal amplitude of both current components. The time course of inactivation was delayed only in the TTX-resistant sodium current. The effect of capsaicin on Na-currents of DRG neurones was similar in guinea-pigs and chicken. In DRG neurones of chicken, only TTX-sensitive currents were observed. In both species the steady-state inactivation of the sodium currents was shifted by capsaicin to more negative potentials.