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When cold becomes hot

Microneurography was originally developed by Vallbo and Hagbarth in the 1960s to bridge the gap between human psychophysical studies and neurophysiological investigations in animal preparations. Soon after the first recordings of single nerve fibre potentials were made in large-diameter myelinated cutaneous and muscle afferents, microneurography was used to examine human C-fibres (e.g. Torebjork, 1974). Despite its technical difficulties and limited yield, microneurography enables an extraordinarily detailed examination of the properties of single fibres in human peripheral nerves in vivo. This intact, physiological protocol can also be used to explore subjective sensations arising from intraneural stimulation of individual nerve fibres, an application ideally suited to the study of pain. These and like studies have helped cement the view that many features of a percept are directly related to the afferent species and its discharge, as much as, if not more than, central mechanisms. 
 
The resurgent field of pain research has been constrained by the difficulty of defining the neural origins of pain to quantify what is ultimately a subjective experience. Functional imaging techniques have provided an objective means to quantify some pain responses and newer techniques have discriminated patterns of responses in the brain arising from selective activation of cutaneous Aδ and C-fibres (Weiss et al. 2008). There are limitations to such techniques: they cannot determine which class or subclass of C-fibre mediates specific pain sensations, such as those evoked by nociceptive thermal stimuli. Most of our present physiological concepts about sensory transduction have been derived from studies in rats, cats and monkeys. However we know there are fundamental differences between animal and human skin. These include the presence of Ruffini endings or slowly adapting type II afferents (SA II) in human glabrous skin, found in neither cat nor monkey; the termination of Aδ fibres in unmyelinated C-fibre type endings; and the strong synaptic coupling between cutaneous afferents, particularly SA IIs, and the motoneurone pool (McNulty & Macefield, 2001). 
 
Behavioural, histochemical and molecular studies in animal models provide a framework on which to explore the structural differences and paradoxical sensations of human skin. In this issue of The Journal of Physiology, Campero et al. (2009) explore one such paradox, that of an unpleasant burning sensation in response to innocuous cooling stimuli. Using microneurography they provide compelling evidence for a specific subclass of C-fibre afferent that responds to both warming and cooling, a class of afferents that they have termed type 2 afferent C fibres (‘C2’). Their intriguing hypothesis is that these fibres do not transduce thermal sensation per se but mediate an unconscious modulation of thermoregulation to preserve homeostatic stability. It implies a trade-off between the metabolic costs of sustaining this sensory channel and the greater efficiency of long-term maintenance within a physiologically safe thermal range. Their findings specifically differentiate between the noxious sensations mediated by type 1 C-fibres and the unpleasant sensations that can sometimes be evoked by apparently innocuous cooling. 
 
The results from this study suggest a simple mechanism to test for interrupted biological functioning of Aδ fibres clinically. The presence of a paradoxical burning sensation in response to a cold stimulus, in the absence of ischaemia, implies the dysfunction of A-fibre signalling (Fruhstorfer, 1984). It is conceivable that thermal dysregulation may be associated with a specific C2 neuropathy. The potential for pharmacological targeting of C2 fibres is raised by the differences in membrane properties of these afferents in comparison to the two classes of type 1 C-fibres (Bostock et al. 2003). This differentiation can only be made using microneurography. 
 
This paper is one of a remarkable series of experiments led by Ochoa and Bostock. The difficulty of recording from single nerve fibres in human peripheral nerves is compounded when specifically targeting type-identified C-fibres, and cannot be overstated. To distinguish the activity of single C-fibres is technically quite challenging using microneurography. The diameter of C-fibres is at least one order of magnitude smaller than Aα and Aβ fibres and their aggregation into Remak bundles further lessens the likelihood of selective recordings. In practice this reduces the ability to distinguish between individual fibres using spike morphology and amplitude, and Campero et al. (2009) have developed sophisticated procedures to assist in this. When this is combined with firing rates <5 Hz and sluggish response times to external thermal and mechanical stimulation, only limited identification is possible based on firing patterns, as is used in microneurographic studies of large-diameter myelinated afferents. Selective recordings of C-fibre potentials therefore rely on the cardinal identifiers of latency and the pattern of activity-dependent slowing in axonal conduction velocity. To distinguish sub-populations of C-fibres unambiguously, an extended sequence of electrical stimulation and baseline recordings is required before the receptive fields can be mapped in response to natural stimuli. Only then can experimental interventions be implemented. The work of Campero and colleagues is the latest in a series of papers that together elucidate the physiological properties of C-fibre afferents in detail similar to that well established for larger diameter afferents.