J Physiol 587.23 (2009) p 5511 5511

PERSPECT IVES

When cold becomes hot

Penelope A. McNulty1 and David Burke2

1Prince of Wales Medical Research Instituteand University of New South Wales, Sydney,Australia2Sydney Medical School, Universityof Sydney, Sydney, Australia

Email: p.mcnulty@powmri.edu.au

Microneurography was originally deve-loped by Vallbo and Hagbarth inthe 1960s to bridge the gap betweenhuman psychophysical studies and neuro-physiological investigations in animalpreparations. Soon after the first recordingsof single nerve fibre potentials were madein large-diameter myelinated cutaneousand muscle afferents, microneurographywas used to examine human C-fibres(e.g. Torebjork, 1974). Despite its technicaldifficulties and limited yield, micro-neurography enables an extraordinarilydetailed examination of the propertiesof single fibres in human peripheralnerves in vivo. This intact, physiologicalprotocol can also be used to explore sub-jective sensations arising from intraneuralstimulation of individual nerve fibres, anapplication ideally suited to the study ofpain. These and like studies have helpedcement the view that many features of apercept are directly related to the afferentspecies and its discharge, as much as, if notmore than, central mechanisms.

The resurgent field of pain researchhas been constrained by the difficulty ofdefining the neural origins of pain toquantify what is ultimately a subjectiveexperience. Functional imaging techniqueshave provided an objective means toquantify some pain responses and newertechniques have discriminated patterns ofresponses in the brain arising from selectiveactivation of cutaneous Aδ and C-fibres(Weiss et al. 2008). There are limitationsto such techniques: they cannot determinewhich class or subclass of C-fibre mediatesspecific pain sensations, such as thoseevoked by nociceptive thermal stimuli. Mostof our present physiological concepts aboutsensory transduction have been derivedfrom studies in rats, cats and monkeys.However we know there are fundamental

differences between animal and humanskin. These include the presence of Ruffiniendings or slowly adapting type II afferents(SA II) in human glabrous skin, found inneither cat nor monkey; the terminationof Aδ fibres in unmyelinated C-fibre typeendings; and the strong synaptic couplingbetween cutaneous afferents, particularlySA IIs, and the motoneurone pool (McNulty& Macefield, 2001).

Behavioural, histochemical and molecularstudies in animal models provide aframework on which to explore thestructural differences and paradoxicalsensations of human skin. In this issueof The Journal of Physiology, Camperoet al. (2009) explore one such paradox,that of an unpleasant burning sensationin response to innocuous cooling stimuli.Using microneurography they providecompelling evidence for a specific sub-class of C-fibre afferent that responds toboth warming and cooling, a class ofafferents that they have termed type 2afferent C fibres (‘C2’). Their intriguinghypothesis is that these fibres do not trans-duce thermal sensation per se but mediatean unconscious modulation of thermo-regulation to preserve homeostatic stability.It implies a trade-off between the metaboliccosts of sustaining this sensory channeland the greater efficiency of long-termmaintenance within a physiologically safethermal range. Their findings specificallydifferentiate between the noxious sensationsmediated by type 1 C-fibres and theunpleasant sensations that can sometimesbe evoked by apparently innocuous cooling.

The results from this study suggest a simplemechanism to test for interrupted biologicalfunctioning of Aδ fibres clinically. The pre-sence of a paradoxical burning sensation inresponse to a cold stimulus, in the absenceof ischaemia, implies the dysfunction ofA-fibre signalling (Fruhstorfer, 1984). It isconceivable that thermal dysregulation maybe associated with a specific C2 neuro-pathy. The potential for pharmacologicaltargeting of C2 fibres is raised by thedifferences in membrane properties of theseafferents in comparison to the two classesof type 1 C-fibres (Bostock et al. 2003).This differentiation can only be made usingmicroneurography.

This paper is one of a remarkable seriesof experiments led by Ochoa and Bostock.

The difficulty of recording from singlenerve fibres in human peripheral nerves iscompounded when specifically targetingtype-identified C-fibres, and cannot beoverstated. To distinguish the activityof single C-fibres is technically quitechallenging using microneurography. Thediameter of C-fibres is at least one orderof magnitude smaller than Aα and Aβ

fibres and their aggregation into Remakbundles further lessens the likelihoodof selective recordings. In practice thisreduces the ability to distinguish betweenindividual fibres using spike morphologyand amplitude, and Campero et al.(2009) have developed sophisticatedprocedures to assist in this. When thisis combined with firing rates <5 Hzand sluggish response times to externalthermal and mechanical stimulation, onlylimited identification is possible basedon firing patterns, as is used in micro-neurographic studies of large-diametermyelinated afferents. Selective recordingsof C-fibre potentials therefore relyon the cardinal identifiers of latencyand the pattern of activity-dependentslowing in axonal conduction velocity. Todistinguish sub-populations of C-fibresunambiguously, an extended sequenceof electrical stimulation and baselinerecordings is required before the receptivefields can be mapped in response to naturalstimuli. Only then can experimentalinterventions be implemented. The workof Campero and colleagues is the latest in aseries of papers that together elucidate thephysiological properties of C-fibre afferentsin detail similar to that well established forlarger diameter afferents.

References

Bostock H, Campero M, Serra J & Ochoa J(2003). J Physiol 553, 649–663.

Campero M, Baumann TK, Bostock H & OchoaJL (2009). J Physiol 587, 5633–5652.

Fruhstorfer H (1984). Pain 20, 355–361.McNulty PA & Macefield VG (2001). J Physiol

537, 1021–1032.Torebjork HE (1974). Acta Physiol Scand 92,

374–390.Weiss T, Straube T, Boettcher J, Hecht H, Spohn

D & Miltner WHR (2008). Neuroimage 41,1372–1381.

C© 2009 The Authors. Journal compilation C© 2009 The Physiological Society DOI: 10.1113/jphysiol.2009.183483