Ligands for opioid and sigma-receptors improve cardiac electrical stability in rat models of post-infarction cardiosclerosis and stress

The effects of the extremely selective mu-opioid receptor agonist, [D-Arg(2 ),Lys(4)] dermorphin-(1-4)-amide (DALDA), the mu-opioid receptor agonist mo rphine, the mu/delta agonist D-Ala(2), Leu(5), Arg-enkephalin (dalargin), t he kappa-opioid receptor agonist spiradoline, and the sigma(1),-receptor an tagonist DuP 734 on ventricular fibrillation threshold (VFT) was investigat ed in an experimental post-infarction cardiosclerosis model and an immobili zation stress-induced model in rats. Both models produced a significant dec rease in VFT. The postinfarction cardiosclerosis-induced decrease in VFT wa s significantly reversed by intravenous administration of dalargin (0.1 mg/ kg), DALDA (0.1 mg/kg), or morphine HCl (1.5 mg/kg). Pretreatment with nalo xone (0.2 mg/kg) completely eliminated the increase in cardiac electrical s tability produced by DALDA. Both spiradoline (8 mg/kg, i.p.) and DuP 734 (1 mg/kg, i.p.) produced a significant increase in VFT in rats with postinfar ction cardiosclerosis. This effect of spiradoline was blocked by nor-binalt orphimine. The immobilization stress-induced decrease in VFT was significan tly reversed by administration of either DALDA, spiradoline or DuP 734. In conclusion, activation of either mu- or kappa(1)-opioid receptors or blocka de of sigma(1)-receptors reversed the decrease in VFT in both cardiac compr omised models. Since DALDA and dalargin essentially do not cross blood brai n barriers, their effects on VFT may be mediated through peripheral mu-opio id receptors. (C) 1999 Elsevier Science Inc.