Chronic neuropathic pain, characterised by allodynia (perception of innocuous stimuli as
painful) and hyperalgesia (facilitated responses to painftil stimuli), is poorly understood and
is usually resistant to classical analgesics. Such abnormal pain phenomena can be associated
with human demyelinating conditions such as Charcot-Marie-Tooth disease. Using mouse
models of peripheral nerve demyelination, we have provided evidence for the consequent
establishment of neuropathic pain and investigated possible underlying mechanisms.
The first model investigated was the Prx-mi\\ mouse. The murine periaxin gene (Prx) is
expressed in Schwann cells and encodes L- and S-periaxin, two abundant PDZ-domain
proteins thought to have a role in stabilisation of myelin in the peripheral nervous system
(PNS). Prx-null mice show progressive demyelination in peripheral nerves and
electrophysiological investigations indicate the presence of spontaneous action potential
discharge; abnormal activity thought to be critical for the development of persistent pain
states. Consistent with the time course of demyelination, Rrx-null mice display an increased
behavioural reflex sensitivity to cutaneous mechanical and noxious thermal stimulation.
To further investigate the link between demyelination of peripheral nerves and neuropathic
pain, we have also characterised a novel model of focal peripheral nerve demyelinating
neuropathy. Focal demyelination of the sciatic or saphenous nerve was induced with
lysolecithin (lysophosphatidylcholine) and resulted in an increased behavioural reflex
sensitivity to both thermal and mechanical tests, peaking at 9-14 days following treatment.
Nerve morphology was investigated using light and electron microscopy, which revealed 30-
40% demyelination of the treated nerve, (without lysolecithin-treated axon loss) coinciding
with peak behavioural changes. Changes in the excitability of saphenous nerves were
revealed, with spontaneous action potential discharge of 2-3 impulses per second present at
peak behavioural change. No associated change in peripheral activation thresholds or
conduction velocity was observedIn both models, immunohistochemical investigations revealed no cell loss in the dorsal root
ganglia (DRG) and no evidence for axonal damage. Similar methods revealed changes in the
expression of neuropeptide Y, and the sodium channels Nav1.3 and Nav1.8 in DRG
neurones. Such changes may account for increased nerve excitability and are known to
occur in other models of nerve injury. However, these changes in the demyelinating models
occur in a more restricted manner, specifically in the cells of formerly myelinated fibres.
Intrathecal injections of the selective NMDA receptor antagonist, [R]-CPP, indicated that
NMDA receptor-dependent changes are crucial for the development of a neuropathic pain
like state following peripheral nerve demyelination. Intrathecal administration of
pharmacological agents indicated a role for the transcription factor NFkB in the production
of the behavioural reflex sensitivity of lysolecithin-treated mice, as well as identifying the
endogenous cannabinoid system as an effective inhibitory regulator and potential analgesic
target.This study describes the first mouse models of peripheral nerve demyelination designed for
the study of neuropathic pain and reveals phenotypic changes in DRG, which may contribute
to the development of a neuropathic pain-like state. Therefore, these models may be useful
for the evaluation of novel therapeutic targets for the treatment of demyelination-associated
neuropathic pain
