Effect of pioglitazone and fluoxetine on neuropathic pain induced exper- imentally in diabetic rats

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.