A. Iggo,     Department of Veterinary Physiology, University of Edinburgh

ABSTRACT

The non-myelinated axons in peripheral nerves were originally reported in 1838 by Remak, although their detailed description had to await the introduction of the electron microscope. Most of them are dorsal root afferent, but some enter the spinal cord via the ventral roots. Their functional characteristics, and particularly the role in pain attracted attention in the 1930′s. The introduction in 1956 of single unit C-fibre recording yielded exact information needed for a satisfactory analysis of the receptor characteristics. A broad survey is made of C-fibre afferents in the viscera, skin and deeper somatic tissues. The action of these C-fibres in the central nervous system, principally in the dorsal horn of the spinal cord is briefly reviewed.

KEYWORDS

Afferent C-fibres

non-myelinated axons

cutaneous receptors

visceral receptors

muscle receptors

INTRODUCTION

The existence in peripheral nerves of very small axons was first demonstrated by Remak in 1838, who microdissected peripheral nerves in water. He saw very fine interlacing filaments with nucleated corpuscles, subsequently found to be Schwann cell nuclei (Fig. 1A). These filaments have become known as Remak bundles or Remak fibres. Tuckett (1895) using a technique of teasing the nerve apart in aqueous humour, was able to distinguish three components in Remak’s fibres – nuclei of the sheath (Schwann) cells, a sheath and the cores of the fibres (Fig. 1B). The C, or more correctly, the non-myelinated (non-medullated, unmyelinated) fibres in peripheral nerve thus have a long scientific history. They were revealed with improved clarity in Ranson’s modification of Cajal’s silver stain for axons. He found them to arise principally from dorsal root ganglion cells (Ranson, 1911) and to be segregated in the lateral division of the spinal dorsal roots in cats and to enter the dorsal horn immediately, or after a short passage in Lissauer’s tract. This separation is clearly marked in primates. It gave an opportunity to assess experimentally their sensory rôle. When this lateral division of the dorsal root was sectioned by Ranson in cats, the ‘pseudo-affective reflexes’ were found to be weaker in response to previously effective noxious stimuli. Although the dorsal root afferents that run into Lissauer’s tract include both small myelinated and non-myelinated axons, the idea was established that the small fibres, including C-fibres, were pain fibres. There are also, of course, numerous C-fibres which are part of the autonomic nervous system.

This classical Bell-Magendie view of the afferent fibres has been modified by the work of Coggeshall and Willis and their colleagues on the spinal ventral roots. These roots have long been known to contain C-fibres and also neuronal cell bodies. Coggeshall, Coulter and Willis (1974) have now established that many ventral root C-fibres are afferent. The C-fibres comprise about thirty per cent of the ventral root fibres and about half of them are sensory. There are therefore substantial numbers of afferent C-fibres that enter the small cord through the ventral roots. Only a very small number of myelinated afferent fibres take the same course (Applebaum and others, 1976). Clifton and others (1976) dealing with the sacral and caudal roots of the cat report that the afferents are distributed widely among the pelvic viscera as well as to the skin and deeper somatic structures. In general they had relatively insensitive receptors. Those in the viscera were either mucosal, responding to severe mechanical stimuli, or were distension sensitive. The new results present a challenge to the classical Bell-Magendie Law but little is yet known of the sensory or reflex functions of the ventral root afferent C-fibres. They could be nociceptors.

ELECTROPHYSIOLOGY. WAVES AND UNIT POTENTIALS

The introduction in 1924–6 by Adrian (1926) of techniques for electrical recording of sensory impulses from nerve endings and particularly the results obtained by Adrian and Zotterman (1926) using a single end organ preparation both heralded a new epoch in neurophysiology and gave promise that the C-fibres would soon reveal their secrets. Not so. In 1931 in his Croonian lecture Adrian was able to surmise that something must be going on in the small fibres, but the capillary electrometer was too insensitive to reveal what it was. In fact, when we consider the kind of evidence provided by the capillary electrometer used in the original studies and Matthews’ oscillograph used for the later studies (Fig. 3), and the constraints they imposed on the investigators, we can only admire the success achieved.

Now enters the C-wave of the compound action potential which has given its name to the laboratory jargon for the non-medullated axons in peripheral nerves. Gasser and Erlanger introduced and developed the application of the cathode-ray oscilloscope and thermionic amplifiers to the point where, in excised peripheral nerves, it was possible to detect, first a synchronous volley of impulses in the largest and fastest myelinated axons (the A wave), then the slower B wave and finally after some doubts and refinement of the techniques, the C-wave (Erlanger and Gasser, 1930). The correlation of these waves with the various sizes of axon in peripheral nerve occupied Erlanger, Gasser and Bishop for several years but the main picture was clear by the time of the publication of Erlanger and Gasser’s monograph in 1937, and the C-wave was established as originating in the non-myelinated axons. In 1955 Gasser returned to the C-fibres and showed in the sural nerve of the cat that they conduct at velocities between 2.3 and 0.6 m/s, thus amending the original conduction rates “of the C-fibres 1.6 – 0.3 m.p.s” (Erlanger and Gasser, 1930).

Meantime, the search for the axons of receptors with high sensitivity to noxious stimuli continued in Europe using the technique of unit recording. An active laboratory in this search was that of our Guest of Honour, Yngve Zotterman. He followed up the advances that flowed from the introduction of Matthews’ sensitive amplifying and recording system that replaced the capillary electrometer. Even with this new device Adrian, Cattell and Hoagland in 1931 were unable to subdue the C-fibres. Meantime, the existence of large and small afferent fibres and their relative sensitivity to conduction block by ischaemia, cold, local anaesthetic and/or pressure had led Zotterman (1933) to give strong support to the view that first and second (burning pain) were due to impulses in myelinated and non-myelinated fibres respectively and thus to promote the view that the C-fibres were pain fibres. Attempts to separate the different waves of the compound action potential in peripheral nerve established that the C-wave was more readily blocked by local anaesthetic and less sensitive to ischaemia than the largest components of the A-wave. This gave promise of an attribution of sensory functions to the C-fibres in peripheral nerves. The A-fibres were already regarded as necessary for tactile sensory inputs. Clarke, Hughes and Gasser in 1935 showed that the C-fibres mediated pain but that the localized cutaneous pain was mediated by small myelinated axones. In man, knowledge about differential block in peripheral nerve of A and C-fibres, as well as the existence of first and second ‘pain’ led to the attribution of second pain to C-fibres by Zotterman in 1933. Even here the claims were contested, and recent single unit studies have shown that differential block by cold (Paintal, 1965; Franz and Iggo, 1968), local anaesthetic (Franz and Perry, 1974) and probably by ischaemia is less selective than once thought. Although A and C-fibres can be separated by selective block (Fig. 4) the various A-fibres cannot, particularly when natural repetitive stimulation via receptors is used as the input. This is due...