Browsing by Subject "delta opioid receptor"
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Item Intermittent hypoxia induced opioidergic protection of the heart(2015-08-01) Estrada, Juan A.; Robert T. Mallet; Steve W. Mifflin; J. Thomas CunninghamNormobaric intermittent hypoxia conditioning (IHC) induces a robust cardioprotected phenotype in dogs that is remarkably resistant to ischemia and reperfusion induced myocardial infarction and lethal arrhythmias. Previous studies demonstrated that IHC induced cardioprotection requires β1-adrenergic receptor activity. Cardiac opioid systems are stimulated by, and counteract the harmful effects of, excessive stressors such as sympathetic activity. Additional modes of hypoxic conditioning have been shown to induce synthesis of cardiac enkephalins and delta opioid receptors (DOR). The hypothesis that DOR mediates IHC cardioprotection was examined in two studies conducted in intermittent hypoxia conditioned and non-hypoxic sham dogs. For the first study dogs were assigned to groups subjected to non-hypoxic sham conditioning, IHC, IHC plus the aminothiol antioxidant N-acetylcysteine (NAC), and IHC plus the DOR antagonist naltrindole. After IHC or sham conditioning, the dogs were subjected to an left anterior descending coronary artery occlusion/reperfusion protocol and incidence of reperfusion arrhythmias and myocardial infarct size were measured and adjusted for coronary collateral flow. Naltrindole and NAC abolished the anti-infarct and anti-arrhythmia effects of IHC, in a manner independent of collateral blood flow. Intermittent hypoxia conditioning is thus dependent on DOR activity as well as formation of reactive oxygen species (ROS) during cylic hypoxia-reoxygenation. Whether ROS are generated upstream, downstream, or in parallel to DOR activation remains to be determined. DORs are abundant on dog parasympathetic nerves and therefore are ideally positioned to stimulate cardioprotective cholinergic activity. However it is unknown in what direction IHC modulates bimodal DORs, i.e. modulation of synaptic inhibitory or excitatory activity. In the second study dogs were assigned to sham conditioned, IHC, and IHC plus naltrindole groups. IHC resulted in a profound enhancement of vagal bradycardia, in the absence and presence of increasingly vagolytic doses of the DOR agonist MEAP. This result demonstrated that IHC shifts DOR signaling in favor of the vagotonic DOR-1 receptor subtype. However, the fate of the vagolytic DOR-2 receptors was unknown. Immunolabeling of atrial tissue revealed that IHC increased content of the monosialoganglioside GM1 in autonomic nerve fibers associated with parasympathetic fibers, an effect which may shift DOR signaling in favor of the DOR-1 subtype. In addition, IHC increased the number of fibers containing the vesicular acetylcholine transporter within the sinoatrial node. However, DOR positive fibers in both the atria and SAN were decreased after IHC, perhaps reflecting redistribution or intracellular trafficking of DOR1 and/or DOR2 receptors. Immunoblotting revealed decreased content of adrenergic protein tyrosine hydroxylase in the left ventricle following IHC. Collectively, these results indicate IHC is dependent on opioidergic activity to induce cardioprotection by enhancing cholinergic signaling components at the expense of adrenergic proteins, suggesting IHC-induced shifting of autonomic balance in favor of parasympathetic control of the heart.Item Opioid Receptors in Aging and Oxidative Stress(2007-01-01) Raut, Atul M.; Ratka, Anna; Simpkins, James W.; Dillon, GlennRaut, Atul M., Opioid Receptors in Aging and Oxidative Stress. Doctor of Philosophy (Pharmacology and Neuroscience), January 2007, 181 pp, 4 illustrations, 21 figures, 159 titles. Oxidative stress has been implicated in aging and neurodegenerative disorders. Pain sensitivity and responses to opioids change with aging. The effect of aging and oxidative stress on opioid receptor system is not yet well understood. To study the effects of aging on pain sensitivity and opioid-induced antinociception, and to determine the possible association of oxidative stress with these pain parameters, in vivo studies were conducted. To further elucidate the effects of oxidative stress on opioid receptor proteins and their function, in vitro studies were carried out. The effects of aging on pain sensitivity and opioid-induced antinociception were studied in male Fischer 344 rats. Oxidative stress markers in cerebral cortex, hippocampus, striatum and midbrain of these rats were estimated. It was concluded that sensitivity to nociceptive stimulus increases and responses to opioids decrease with aging and age-related oxidative damage is negatively correlated with opioid-induced antinociception. To characterize the effects of oxidative stress on function of opioid receptors, changes in intracellular cyclic adenosine monophosphate (cAMP) was measured in human SK-N-SH neuronal cells under oxidative stress conditions. It was found that oxidative stress decreased the function of mu opioid receptor (MOR) but not that of delta or kappa opioid receptors (DOR and KOR respectively). Antioxidant intervention preserved the function of MOR. Western immunoassays revealed that MOR but not DOR and KOR proteins were decreased under oxidative stress conditions. Thus, these findings show a selective impairment of the MOR function and reduction in MOR protein under conditions of oxidative stress. The results from the in vivo and in vitro projects demonstrate the involvement of aging and oxidative stress in modulation of pass sensitivity, opioid-induced antinociception and opioid receptor function and expression.