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PERSPECTIVES |
1 Institute of Clinical Neurosciences, University of Sydney and Royal Prince Alfred Hospital, Sydney, New South Wales 2006, Australia
Email: d.burke{at}med.usyd.edu.au
Axons have one main role: to transmit a nerve impulse securely from one end to the other with minimal expenditure of energy. To do this they have a complex structure and are endowed with a variety of ion channels, pumps and exchangers (see Waxman et al. 1995). Knowledge of axonal properties is important because many disease processes are primarily diseases of white matter, affecting the axon rather than the cell body: multiple sclerosis, forms of stroke, spinal cord injury, to name just a few. It is clear that the extent of deficit can be limited in, for example, primarily demyelinating diseases, by controlling the cascade that leads to axonal degeneration (Waxman, 2006). Elucidating the molecular mechanisms determining axonal excitability and how they alter with activity could allow therapeutic strategies to be targeted quite specifically to rescue axons in, for example, multiple sclerosis and spinal injury, or to dampen down excessive impulse traffic associated with, for example, paraesthesiae and pain.
It seems trite to say that axons of different modality differ: with cutaneous afferents in peripheral nerves, there is the well-known correlation between function and size, with discriminative tactile sensations reliant on large myelinated axons and with thermal and nociceptive sensations dependent on small myelinated and unmyelinated axons. Comparable size-related specializations occur within muscle afferents and in motor axons.
It is intuitively reasonable that the stresses caused by conducting impulses will require a different molecular solution for axons that are required to maintain different patterns of impulses, regardless of size and myelination. There may be subtle but significant differences in the biophysical properties of axons of comparable size but different function. These differences result in different changes in excitability when the axons are active, and could predispose some axons to dysfunction more than others.
In human subjects, large myelinated cutaneous afferents are of similar size to large myelinated alpha motor axons, but there are a number of differences in their properties (summarized in Burke et al. 2001; Kiernan et al. 2005). In particular, it seems that the expression of two depolarizing conductances, a persistent Na+ current and the hyperpolarization-activated conductance (IH), is greater on cutaneous afferents. There is also evidence that cutaneous afferents have greater dependence on the electrogenic Na+/K+ pump to maintain membrane potential, possibly compensation for the greater resting Na+ influx conferred by the greater persistent Na+ current. These differences would render cutaneous afferents both more excitable and more resistant to the hyperpolarizing stresses that occur when axons conduct impulse trains. As a result, ectopic activity would occur more readily with cutaneous afferents and, indeed, nerve injury produces paraesthesiae more readily than fasciculation. Conversely, at sites of lowered safety margin for impulse conduction, motor axons would be more likely to develop conduction block when transmitting impulse trains. In addition to modality-specific differences, there are (i) differences between cutaneous afferents innervating different skin regions, such as the sural nerve and the median nerve, with evidence for a lesser slow K+ conductance and lesser IH on sural afferents, and (ii) changes in some axonal properties along the length of the axon.
The study of George et al. (2007) in this issue of The Journal of Physiology extends these observations, by demonstrating that, for C fibres innervating the skin of the lower leg and foot of the rat, there is a correlation between functional subclass and biophysical properties. C fibres could be identified functionally with reasonable confidence as mechano-responsive nociceptors, mechano-insensitive nociceptors, cold-responsive afferents, sympathetic efferents or unknown, and each group underwent a distinctive change in conduction velocity following a single discharge (or two discharges), and when the overall repetition rate was increased to produce axonal hyperpolarization. Even within nociceptive afferents, there were subtle differences dependent on whether the afferent was mechano-responsive or not. These findings confirm for rat C fibres earlier findings for human C fibres (Weidner et al. 2000; Bostock et al. 2003).
The findings of George and colleagues are important for a number of reasons. The postdischarge changes in excitability will mean that stimulus transduction may vary with activity, differently for different C fibre subclasses, and that there may also be differences in action potential propagation as terminal branches join to form the axon. The distinctive behaviour of nociceptive afferents may indicate a unique property that could be a potential pharmacological target – though it will be necessary to identify the biophysical basis of the differences in postdischarge behaviour before this potential can be realized. Finally, the findings add to the growing body of evidence indicating that biophysical properties may be adapted to function.
It is an attractive hypothesis that these differences represent adaptations to the discharge patterns and discharge rates of the axons, adaptations designed to ensure that the conduction of a normal discharge is secure. If so, this raises further issues. For example, there are four different types of large myelinated afferent innervating the glabrous skin of the human hand. Each has a distinctive discharge pattern, and one would therefore expect there to be differences in their behaviour in measures of axonal excitability, particularly those that are activity dependent. To address this issue in human subjects would be technically demanding, requiring microneurography, large samples of afferents of each subclass and stable recordings for sufficiently long to characterize each afferent's behaviour. It might be more feasible to approach the issue directly in animal experiments, with identified single afferents.
References
Bostock H, Campero M, Serra J & Ochoa J (2003). J Physiol 553, 649–663.
Burke D, Kiernan MC & Bostock H (2001). Clin Neurophysiol 112, 1575–1585.[CrossRef][Medline]
George A, Serra J, Navarro X & Bostock H (2007). J Physiol 578, 213–232.
Kiernan MC, Burke D & Bostock H (2005). In Peripheral Neuropathy, ed. Dyck PJ & Thomas PK, vol. 1, pp. 113–129. Elsevier, Amsterdam.
Waxman SG (2006). Trends Molec Med 12, 192–195.[CrossRef]
Waxman SG, Kocsis JD & Stys PK (ed) (1995). The Axon: Structure, Function and Pathophysiology. Oxford University Press, New York.
Weidner C, Schmidt R, Schmelz M, Hilliges M, Handwerker HO & Torebjörk HE (2000). J Physiol 527, 185–191.
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