Biology Reference
In-Depth Information
secrete a host of immune mediators, which include the pro-
inflammatory cytokines interleukin (IL) 1
β
, IL6, and tumor necro-
sis factor
) as well as reactive oxygen species (
11, 23
).
Such immune mediators are considered to be important in the
development of pain behavior in the neuritis model, since the
administration of antagonists or scavengers against these compo-
nents can prevent mechanical allodynia (
24
). In line with their
likely role in the mechanisms of pain behavior, both TNF
α
(TNF
α
α
and
IL1
are reported to induce ongoing activity in sensory axons fol-
lowing direct exposure (
25-27
). More specifically, in the neuritis
model, TNF
β
and the chemokine CCL2 may act to modulate
ongoing activity in C-fiber neurons that are already modified by
the inflammatory process (
19
).
Another prominent electrophysiological feature of the neuritis
model is the development of axonal mechanical sensitivity at the
treatment site, whereby axons respond to direct mechanical stimu-
lation. Similar to ongoing activity, axonal mechanical sensitivity
also peaks within a week of neuritis induction (
10, 12, 17, 28
).
Axonal mechanical sensitivity develops along intact, uninjured C- and
A-fiber axons, thereby contrasting from the original findings in the
nerve injury models where it was the tips of degenerated axons that
became sensitive to mechanical stimulation (
4, 7
). Clinically, axonal
mechanical sensitivity corresponds to movement-evoked radiating
pain that is reported by patients. Axonal mechanical sensitivity
most likely results from the inflammation-induced disruption of
axoplasmic transport, whereby mechanosensitive channel compo-
nents that are transported along axons towards the terminals
dam up at the site of the neuritis. This accumulation leads to a “hot
spot” of mechanosensitivity (
29
).
Whilst the majority of studies have examined the role of
inflammation in the development of axonal hyperexcitability and
pain behaviors, investigations into the role of neuroprotective
agents in the neuritis model have yet to be published. Of interest
is the role of erythropoietin and its derivative ARA290 in
inflammatory pain pathways (reviewed by Swartjes and colleagues
in Chapter
12
). Previous studies that have focused on nerve injury
models (chronic constriction injury, spinal nerve crush, and spared
nerve injury) have demonstrated the reversal of pain behavior fol-
lowing the administration of erythropoietin or ARA290 (
30-32
).
Based on these observations, such agents can undoubtedly pro-
vide a protective role in pain pathways. The data presented in this
chapter demonstrates the potential benefits of ARA290 in the
neuritis model, where there is no apparent nerve injury. It pro-
vides detailed methodology for inducing the neuritis and testing
heat hyperalgesia, as well as an alternative method to that described
by Swartjes and colleagues (Chapter
12
) for examining mechani-
cal allodynia.
α
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