Abstract
Diabetic neuropathic pain, an importantmicrovascular complicationindiabetes mellitus, is recognized asoneof the most difficult types of paintotreat due to underlying neuralpathologicalchanges such as inflammationand fibrosis. It is not possibletouse a single drug as a first-linetreatmentfor diabetic peripheral neuropathicpain. The aim of this work istostudy the neural pathologicalchangesand tissue levels of proinflammatorycytokines, TNF-αand IL6that may underlie the differenttypesof neuropathic pain (tactile allodyniaand thermal hyperalgesia)andto explore the effects of pioglitazoneand/or fluoxetine on thesechanges.Sixty adult male white albinorats were assigned into two maingroups,diabetic group with induction of diabetes by single intra-peritonealinjection of streptozotocin with highcholesterol diet and non-diabeticgroup fed on normal diet. Each maingroup was divided into subgroups(n=6 rats each) as follows: [I] control,with no treatment; [II] subjected toperipheral sciatic nerve ligation(PSL) only with no treatment; [III]PSL with pioglitazone treatment; [IV]PSL with fluoxetine treatment and[V] PSL with pioglitazone and fluoxetinecombined treatment. All subgroupswere tested before, at day 7andday14 after PSL for tactile allodyniaand thermal hyperalgesia followedby measurement of nerve tissuelevels of TNF-α and IL-6,quantification of collagen depositionand macrophages counting. Wefound that PSL significantly increasedinflammatory cell infiltration mainly macrophages and collagendeposition with significant increaseof nerve tissue levels of TNF-α andIL-6 in both groups. These changeswere associated with significant increaseof tactile allodynia and thermalhyperalgesia. Administration ofpioglitazoneand/or fluoxetine significantlydecreased both macrophagesinfiltrationand collagen depositionandnerve tissue levels of TNF-αandIL-6.These effects were associatedwithsignificant attenuation of tactileallodyniaand thermal hyperalgesiaproducedby PSL in both diabeticandnon-diabetic groups but fluoxetinealone had weaker effect in diabeticgroup. These results suggestedthatmacrophages infiltration and collagendeposition with associated elevationof tissue proinflammatory cytokinescould be a cause ofneuropathicpain and administrationof pioglitazone and fluoxetine can attenuateneuropathic pain by abolishingthese changes.
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