κ-Opioid receptor stimulation modulates TLR4/NF-κB signaling in the rat heart subjected to ischemia-reperfusion

It is well documented that the Toll-like receptor 4 (TLR4)/NF-kappa B signaling mediates early inflammation during myocardial ischemia and reperfusion. Our previous study has demonstrated that kappa-opioid receptor stimulation with U50,488H produces cardioprotective and anti-inflammatory effects. The aim of the present study was to investigate whether kappa-opioid receptor stimulation could modulate the TLR4/NF-kappa B signaling and reduce neutrophil accumulation and TNF-alpha induction in an ischemia-reperfusion injured rat heart model. Rats were randomly exposed to sham operation, myocardial ischemia and reperfusion (MI/R), and MI/R + U50,488H in the absence or presence of Nor-BNI, a selective kappa-opioid receptor antagonist. The results demonstrated that after MI/R, the expressions of myocardial TLR4 and NF-kappa B increased significantly both in ischemia area and risking area. Compared with MI/R, kappa-opioid receptor stimulation with U50,488H significantly attenuated the expressions of TLR4 and NF-kappa B. At the mean time, it also reduced myeloperoxidase (MPO) levels, both serum and myocardial TNF-alpha production, myocardial infarct sizes (INF/AAR%) and myocardial apoptosis induced by MI/R, all the effects of U50,488H were abolished by Nor-BNI. These data provide evidence for the first time that kappa-opioid receptor stimulation inhibits TLR4/NF-kappa B signaling in the rat heart subjected to MI/R. 2013 Elsevier Ltd. All rights reserved.