Opioids/opiates are commonly administered to alleviate pain, unload the heart, or decrease breathlessness in patients with advanced heart failure. As such, it is important to evaluate whether the myocardial opioidergic system is altered in cardiac disease. A hamster model of spontaneous hypertension was investigated prior to the development of hypertension (one month of age) and in the hypertensive state (ten months of age) to evaluate the effect of prolonged hypertension on myocardial opioidergic activity. Plasma -endorphin was decreased prior to the development of hypertension and in the hypertensive state (p<0.05). There was no change in cardiac-endorphin content at either time point. No differences were detected in cardiac or plasma dynorphin A, met-enkephalin, or leu-enkephalin, or in cardiac peptide expression of kappa or delta opioid receptors. Mu opioid receptor was not detected in either model. To determine how hypertension affects myocardial opioid signaling, the ex vivo work-performing heart was used to assess the cardiac response to opioid administration in healthy hearts and those subjected to chronic hypertension. Agonists selective for the kappa and delta, but not mu, opioid receptors induced a concentration-dependent decrease in cardiac inotropy and lusitropy. The decrease in LVSP upon administration of the kappa opioid receptor-selective agonist, U50488H, was attenuated in hearts from hamsters subjected to chronic, untreated hypertension (p<0.05) compared to control. These results show that peripheral and myocardial opioid expression and signaling are altered in hypertension.