Cardioprotective Properties of Opioid Receptor Agonists in Rats With Stress-Induced Cardiac Injury

The objectives of this study were to investigate the role of endogenous opioids in the mediation of stress-induced cardiomyopathy (SIC), and to evaluate which opioid receptors regulate heart resistance to immobilization stress. Wistar rats were subjected to 24 h immobilization stress. Stress-induced heart injury was assessed by 99mTc-pyrophosphate accumulation in the heart. The opioid receptor (OR) antagonists (naltrexone, NxMB – naltrexone methyl bromide, MR 2266, ICI 174.864) and agonists (DALDA, DAMGO, DSLET, U-50,488) were administered intraperitoneally prior to immobilization and 12 h after the start of stress. In addition, the selective µ OR agonists PL017 and DAMGO were administered intracerebroventricularly prior to stress. Finally pretreatment with guanethidine was used. Naltrexone did not alter the cardiac 99mTc-PP accumulation in stressed rats. NxMB aggravated stress-induced cardiomyopathy (P=0.005) (SIC). The selective µ OR agonist DALDA, which does not cross the blood-brain barrier, completely prevented (P=0.006) SIC. The µ OR agonist DAMGO exhibited weaker effect than DALDA. The selective δ ligand (DSLET) and κ OR ligand (U-50,488) did not alter stress-induced 99mTc-pyrophosphate accumulation in the heart. Intracerebroventricular administration of the µ OR agonists aggravated SIC. Pretreatment with guanethidine abolished this effect (P=0.01). Guanethidine alone exhibited cardioprotective properties. A stimulation of central µ OR promotes an appearance of SIC. In contrast, stimulation of peripheral µ OR contributes to an increase in cardiac tolerance to stress.

Opioids modify the release of LH at the pituitary level: in vitro studies with entire rat pituitaries

It is currently accepted that opioids modify the secretion of LH by affecting the release of GnRH in the hypothalamus. A direct action of opioids at the pituitary level is not yet fully established. To this end, we tested the effects of opioids on the release of LH by the entire pituitary in adult male rats. Opioid agonists with mu (DAGO), delta (DSLET) and kappa (U-50488H) specificity were tested at 0·01 to 10 μm in static incubations. DAGO inhibited dose-dependently the spontaneous and GnRH-induced release of LH. DSLET inhibited only the GnRH-induced release of LH. On the other hand, U-50488H increased spontaneous LH release dose-dependently. The opioid antagonists naloxone, diallyl-G (delta antagonist) and MR 2266 (kappa antagonist) blocked the effects induced by DAGO, DSLET or U-50488H respectively, implying an opioid receptor-mediated effect. The above results showed that opioids with mu, delta and kappa specificity act on the entire pituitary and modify differentially the release of LH. In this study we also compared spontaneous and GnRH-induced LH release by anterior and entire pituitaries and found that the amount of LH released by the anterior lobe was twofold higher, suggesting that inhibitory factors present in the neurointermediate part may affect the release of LH. Journal of Endocrinology (1995) 145, 263–270

14-β-Methyl-8-oxacyclorphan (BC-3016), a morphinan derivative with high affinity for kappa opioid receptor: comparison with dynorphin-A(1–13)

14-β-Methyl-8-oxacyclorphan (BC-3016) was tested for its ability to depress the electrically evoked contractions of the guinea pig ileum (GPI) and of the mouse vas deferens (MVD) and to compete with the binding of prototype ligands selective for κ-, μ-, or δ-opioid receptors in membrane preparations of rat brain and guinea pig cerebellum. BC-3016 was a very potent agonist in the GPI and MVD preparations, with ID50 of 0.7 and 31 nM, respectively. The activity of levorphanol, a standard alkaloid related to BC-3016, was much lower in both assays with ID50 values of 44 and 86 nM, respectively. Conversely, the activity of BC-3016 was quite comparable to that of dynorphin-A(1–13) in both preparations. In the GPI assay, a putative κ-receptor antagonist, MR-2266, was 6.6 and 5.5 times more potent than naloxone in blocking the activity of BC-3016 and dynorphin-A(1–13), respectively. BC-3016 was also very potent in displacing bound [3H]ethylketocyclazocine ([3H]EKC) to membrane preparations of the guinea pig cerebellum, a brain component containing predominantly κ-opioid receptors (Ki of 0.58 nM). Its potency in the displacement of the bound μ-ligand, 3H-labelled (D-Ala2,MePhe4,Gly-OH5)-enkephalin ([3H]DAGO), to rat brain homogenates was somewhat lower (Ki of 0.8 nM) but still high when compared with its ability to displace the δ-ligand, 3H-labelled (D-Ser2, Thr6)-Leu-enkephalin ([3H]DSLET) to rat brain homogenates (Ki of 4.45 nM). The affinity of BC-3016 for the opioid receptor was 2.1-fold higher than that of U-50488H, a selective κ-opioid ligand. Finally, the relative potency of BC-3016 to bind each one of the receptor types was similar to that of dynorphin-A(1–13). These data indicate that the structural modifications of levorphanol leading to BC-3016 increases the affinity of the compound for the κ-opioid receptor and provides a compound whose profile of activity is similar in some respect to that of endogenous dynorphin-A(1–13).