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J Physiol 586.9 (2008) pp 2247–2248 2247
JOURNAL CLUB
How does inflammation affect mechanical sensitivity and fast axonal vinblastine that were adopted in their study
axonal excitability to mechanical transport, suggested by amalgamating were below those that have been shown
stimulation of neurones in the individual conclusions from previous by numerous independent studies to cause
rat pain pathway? literature, is valid and causal. axonal death and concomitant neuritis.
To answer their question Dilley & Bove Nevertheless, to exclude such confounding
Puja R. Mehta1 and Arpan R. Mehta2
1
(2008) performed two key experiments on factors, Dilley & Bove (2008) performed
Molecular Physiology Group, Department
intact adult rat nociceptive C-fibres from nerve conduction studies through the sites
of Biological Sciences, University of
sciatic nerves exposed to low concentrations treated with colchicine and vinblastine and
Warwick, Coventry CV4 7AL, UK
2
of two pharmacological anti-microtubule also examined the nerves microscopically
Medical Sciences Division, University
agents known to block axonal transport for any signs of neuropathology. It cannot
of Oxford, John Radcliffe Hospital,
(either 10 mm colchicine or 0.1 mm be ruled out that the anaesthetic used had
Oxford OX3 9DU, UK
vinblastine). Mechanical stimulation no effect on results, but the authors made
Email: arpan.mehta@medschool.ox.ac.uk involved the use of a soft probe that any such effect less likely by the use of a
precluded any direct axonal damage from ‘sham’ group, where the same surgery was
occurring. Electrophysiological single-unit carried out on the sciatic nerve but without
recordings from C-fibres, identified by application of any pharmacological agents.
The causes of peripheral neuropathy are their conduction velocities being less than We highlight three important results from
varied, encompassing inflammation, nerve 1.5 ms−1 , were taken at appropriate times Dilley & Bove’s paper. First, both of the
compression, laceration or entrapment and after surgery when blockade of axonal anti-mitotic agents caused AMS to develop,
exposure to toxins. These are not mutually transport was thought to be maximal. albeit in around only a third of intact
exclusive and the mechanisms behind such By the principle of a relative refractory axons (similar to Koschorke et al. (1994)
neuropathies are incompletely understood. period, Dilley & Bove (2008) determined who reported a figure of 23%). This effect
However, numerous studies have shown that whether mechanically and electrically was not seen in the sham group. Second,
at sites of neural inflammation, or neuritis, evoked responses were from the same assuming that these two agents cause axonal
a sensitivity to mechanical stimulation neurone. AMS was defined by the presence transport to be disrupted, the results from
is induced in intact, through-conducting of one or more action potentials during the control experiments showed that the AMS
axons. Such changes in axonal excitability 1–2 s period of mechanical stimulation of was induced in the absence of significant
are of considerable clinical importance the nerve. drug-induced toxicity to the neurones.
because they may explain the typical The first experiment tested whether There was minimal axonal degeneration,
presentation – of radiating pain evoked disruption of axonal transport, determined from both the measurement
by mechanical tension of affected nerves experimentally induced by colchicine of fibres with through-conduction across
– by patients suffering from common and vinblastine treatment, is sufficient to the treatment site, and the lack of
chronically painful conditions. This pain induce AMS. A second experiment was recruitment of ED1-positive macrophages
is sometimes elicited by neurologists in then designed to test whether neuritis that would be predicted to occur as part
the outpatient clinic and is called the leads to AMS that could be explained by of a cell-mediated inflammatory response.
Hoffmann-Tinel sign. Dilley & Bove in a a mechanism involving axonal transport. However, conduction velocity across the
recent paper in The Journal of Physiology Axoplasmic transport was blocked, as in treatment site was significantly reduced
investigate a possible mechanism for the first experiment, but this was localized and the reason given was that minor
explaining such neuritic axonal mechanical carefully to a site upstream from, and inflammation during surgery might have
sensitivity (AMS) in a rat model. The proximal to, the neuritic part of the nerve; occurred. The implication as presented
authors use an integrative approach, the inflammation had been experimentally in the paper of these two results taken
combining electrophysiological, immuno- induced via the application of Complete together is that, all other factors being equal,
histochemical and histological cellular Freund’s Adjuvant, known to encourage the disruption of axonal transport causes AMS
methods to test their hypothesis that production of a cell-mediated inflammatory to occur. The use of two similar types
disruption of fast axonal transport by response. Mechanical stimulation was in of pharmacological agents allows for the
localized neuritis is sufficient to cause the this case only applied to the neuritic effects of one to be compared against the
accumulation, and subsequent membrane part of the nerve, distal to the locus of other and since they both induced a similar
insertion, of mechanosensitive ion channels. pharmacological blockade by vinblastine of effect, it is likely that the cause of the
This hypothesis builds on previous studies axonal transportation, and simultaneous effect is a factor common to both drugs
from other research groups that suggest electrophysiological recordings were made – suppression of axonal transport. Third,
that the rapid inflammatory mediator, to measure AMS. blockade of axoplasmic transport upstream
histamine, disrupts axonal transport and To validate their approach, which relied of an experimentally induced neuritis
that, at least in the monkey, the requisite on the use of pharmacological agents significantly reduced AMS caused by the
components for mechanical sensitivity that are unlikely to be totally specific in neuritis per se, which is concordant with the
are transported by fast axonal transport. their mechanism of action, Dilley & Bove view that the components required for AMS
Dilley & Bove (2008) essentially ask (2008) carried out some crucial control are transported by anterograde fast axonal
whether this link, between inflammation, experiments. The doses of colchicine and transport. Thus, the components required
C 2008 The Authors. Journal compilation C 2008 The Physiological Society DOI: 10.1113/jphysiol.2008.152645
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2248 Journal Club J Physiol 586.9
for AMS were prevented from being trans- The authors state that inflammation of treatment is unsatisfactory, could be better
ported to the neuritic part of the nerve. It unmyelinated fibres causes similar changes managed via the use of anti-inflammatory
is significant that the authors used caution in conduction velocity (Dilley et al. 2005) agents aimed at reversing the cause of
when applying vinblastine to the nerve, since and that the surgical procedure of sciatic the pain. This may even alleviate central
such a drug may dampen inflammation by nerve exposure may have caused minor neuropathic pain in addition to peripheral
altering microtubule assembly and related inflammation to occur, presumably around neuropathy, since abolishing the peripheral
migration of neutrophils. Accordingly, care the nerve. This could have been confirmed inputs to the central nervous system can
was taken to prevent contamination of the by performing nerve conduction studies to reduce symptoms of pain (Gracely et al.
distal (neuritic) portion of the nerve. To obtain conduction latencies on the sham 1992). Future work should be therefore
this end, any anti-inflammatory action of group, where the prediction would be aimed at determining the cause of nerve
vinblastine that might have confounded that the surgical procedure alone causes a inflammation in patients displaying the
the results in an experiment specifically decrease in conduction velocity similar to Hoffmann-Tinel sign. Finally, Dilley &
investigating the role of inflammation in that seen in the results of the colchicine- and Bove (2008) provide some evidence for the
AMS was minimized; it was noted by the vinblastine-treated sciatic nerves; however, mechanism by which vinblastine and other
authors that upon dissection of the neuritic these additional studies were not carried vinca alkaloids might cause the commonly
site, the nerve’s surface appeared highly out. Nevertheless, it is true that even if reported side-effects of diffuse painful
vascularized, suggesting that macroscopic minor local inflammation had occurred neuropathic symptoms in patients afflicted
inflammation had occurred. due to surgery, it is unlikely that that alone with cancers treated by such drugs, with the
Dilley & Bove (2008) therefore could explain the large AMS effect that was caveat that clinical doses may be causing
demonstrate that AMS occurs in nociceptive measured after colchicine and vinblastine direct toxicity to nerves in addition to
C-fibre axons owing to the application treatment, since this effect was not seen in exerting an effect on axoplasmic transport.
of colchicine and vinblastine, assumed the sham group. Future work in this field has the rewarding
solely to disrupt axoplasmic transport. Dilley & Bove (2008) show – for the possibility of being able to better control
Proske & Luff (1998) showed previously first time – that blocking axoplasmic the chemotherapy-induced pain through
that colchicine can induce AMS in cat transport with vinblastine, upstream of the greater understanding of cause–effect
muscle afferents. However, Dilley & Bove an area of experimentally induced neural relationships.
(2008) aimed to further the field by testing inflammation, reduces AMS in that neuritic
whether disruption of axoplasmic transport area. This finding complements and extends
is sufficient to cause AMS. We would previous studies by showing that the AMS
References
argue that one cannot fulfil such an aim that should occur in neuritis does not occur
using the set-up in Dilley & Bove (2008), when fast axonal transport is prevented from Campbell JN & Meyer RA (2006). Mechanisms
simply because it cannot be unequivocally ferrying the components necessary for AMS of neuropathic pain. Neuron 52, 77–92.
shown that colchicine and vinblastine do to the mechanically stimulated neuritic site. Dilley A & Bove GM (2008). Disruption of
not exert any extra-microtubular effects; Dilley & Bove’s results buttress the axoplasmic transport induces mechanical
the syllogism: (1) colchicine/vinblastine suggestion that AMS is caused by the ectopic sensitivity in intact rat C-fibre nociceptor
axons. J Physiol 586, 593–604.
causes AMS; (2) colchicine/vinblastine accumulation of mechanically sensitive ion
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causes disruption of axoplasmic transport; channels at the site of blockade of fast axonal stretch mechanosensitivity of peripheral nerve
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across the treatment site. It is possible see whether AMS, owing to disruption in
to primary afferent terminals by fast axonal
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C 2008 The Authors. Journal compilation C 2008 The Physiological Society
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