RETRACTED: Increases in inflammatory mediators in DRG implicate in the pathogenesis of painful neuropathy in Type 2 diabetes (Retracted article. See vol. 110, pg. 483, 2018)

Background: Painful neuropathy is a common, difficult to treat complication of both Types I and 2 diabetes (T1D and T2D). Reports have shown that activation of inflammatory cascades play an important role in the development and persistence of neuropathic pain states, but it is not well established in painful diabetic neuropathy (PDN). Previously, studies have shown increased inflammatory cytokines in the serum of the diabetic patients with painful neuropathy. This study focuses on the changes in the levels of inflammatory mediators such as TNF alpha, interleukins, chemokines and cell adhesion molecules with the development of pain in the DRG of the Zucker diabetic fatty (ZDF) rat, an established model for T2D. This study also demonstrates an alteration in the levels of voltage gated sodium channel 1.7 (Na(v)1.7) with the development of pain in DRG of the ZDF rats. Results: Pre-diabetic ZDF animals at 8-9 weeks of age showed no thermal and mechanical hyperalgesia compared to their respective lean controls. Diabetic-ZDF animals tested for pain related behaviors showed significant thermal and mechanical hyperalgesia at 4 and 6 weeks after the onset of diabetes when compared with their age matched lean controls. These ZDF animals with PDN also showed changes in a large number of inflammatory mediators in the DRG as assessed by Western blot as well as by cytokine antibody array compared to their age matched lean controls. Further analysis by Rat cytokine antibody array of DRG of the ZDF animals with PDN at 6 weeks after diabetes when compared with ZDF animals with no pain revealed an elevation of a significant number of inflammatory mediators including, the pro-inflammatory cytokines such as TNF alpha, interleukin-1, 6, 13 and 17, chemokines such as MIP1 and 3, RANTES, Fractalkine and cell adhesion molecule sICAM that are associated with pain phenotype. The ZDF animals with PDN also demonstrated an increase in the protein levels of voltage gated sodium channel Na(v)1.7 in DRG compared to lean controls with no pain. Conclusions: The rise in inflammatory markers in the DRG of Type 2 diabetic animals and increases in voltage gated sodium channel Na(v)1.7 in DRG with the onset of pain in PDN suggest that inflammation in the DRG may play an important role in the development of pain in this model. Published by Elsevier Ltd.