Diabetic neuropathic pain, an important
microvascular complication
in
diabetes mellitus, is recognized as
one
of the most difficult types of pain
to
treat due to underlying neural
pathological
changes such as inflammation
and fibrosis. It is not possible
to
use a single drug as a first-line
treatment
for diabetic peripheral neuropathic
pain. The aim of this work is
to
study the neural pathological
changes
and tissue levels of proinflammatory
cytokines, TNF-α
and IL6
that may underlie the different
types
of neuropathic pain (tactile allodynia
and thermal hyperalgesia)
and
to explore the effects of pioglitazone
and/or fluoxetine on these
changes.
Sixty adult male white albino
rats were assigned into two main
groups,
diabetic group with induction of diabetes by single intra-peritoneal
injection of streptozotocin with high
cholesterol diet and non-diabetic
group fed on normal diet. Each main
group was divided into subgroups
(n=6 rats each) as follows: [I] control,
with no treatment; [II] subjected to
peripheral sciatic nerve ligation
(PSL) only with no treatment; [III]
PSL with pioglitazone treatment; [IV]
PSL with fluoxetine treatment and
[V] PSL with pioglitazone and fluoxetine
combined treatment. All subgroups
were tested before, at day 7
and
day14 after PSL for tactile allodynia
and thermal hyperalgesia followed
by measurement of nerve tissue
levels of TNF-α and IL-6,
quantification of collagen deposition
and macrophages counting. We
found that PSL significantly increased
inflammatory cell infiltration mainly macrophages and collagen
deposition with significant increase
of nerve tissue levels of TNF-α and
IL-6 in both groups. These changes
were associated with significant increase
of tactile allodynia and thermal
hyperalgesia. Administration of
pioglitazone
and/or fluoxetine significantly
decreased both macrophages
infiltration
and collagen deposition
and
nerve tissue levels of TNF-α
and
IL-6.
These effects were associated
with
significant attenuation of tactile
allodynia
and thermal hyperalgesia
produced
by PSL in both diabetic
and
non-diabetic groups but fluoxetine
alone had weaker effect in diabetic
group. These results suggested
that
macrophages infiltration and collagen
deposition with associated elevation
of tissue proinflammatory cytokines
could be a cause of
neuropathic
pain and administration
of pioglitazone and fluoxetine can attenuate
neuropathic pain by abolishing
these changes.