Activation of peripheral opioid κ1 receptor prevents cardiac reperfusion injury

Abstract

The role of opioid κ1 and κ2 receptors in reperfusion cardiac injury was studied. Male Wistar rats were subjected to a 45-min coronary artery occlusion followed by a 120-min reperfusion. Opioid κ receptor agonists were administered intravenously 5 min before the onset of reperfusion, while opioid receptor antagonists were given 10 min before reperfusion. The average value of the infarct size/area at risk (IS/AAR) ratio was 43 – 48 % in untreated rats. Administration of the opioid κ1 receptor agonist (-)-U-50,488 (1 mg/kg) limited the IS/AAR ratio by 42 %. Administration of the opioid κ receptor agonist ICI 199,441 (0.1 mg/kg) limited the IS/AAR ratio by 41 %. The non-selective opioid κ receptor agonist (+)-U-50,488 (1 mg/kg) with low affinity for opioid κ receptor, the peripherally acting opioid κ receptor agonist ICI 204,448 (4 mg/kg) and the selective opioid κ2 receptor agonist GR89696 (0.1 mg/kg) had no effect on the IS/AAR ratio. Pretreatment with naltrexone, the peripherally acting opioid receptor antagonist naloxone methiodide, or the selective opioid κ receptor antagonist nor-binaltorphimine completely abolished the infarct-reducing effect of (-)-U-50,488 and ICI 199,441. Pretreatment with the selective opioid δ receptor antagonist TIPP[ψ] and the selective opioid µ receptor antagonist CTAP did not alter the infarct reducing effect of (-)-U-50,488 and ICI 199,441. Our study is the first to demonstrate the following: (a) the activation of opioid κ2 receptor has no effect on cardiac tolerance to reperfusion; (b) peripheral opioid κ1 receptor stimulation prevents reperfusion cardiac injury; (c) ICI 199,441 administration resulted in an infarct-reducing effect at reperfusion; (e) bradycardia induced by opioid κ receptor antagonists is not dependent on the occupancy of opioid κ receptor.