enkephalin--leucine-2-alanine and tyrosyl-arginyl-phenylalanyl-lysinamide

The effects of the extremely selective mu-opioid receptor agonist, [D-Arg2,Lys4]-dermorphin-(1-4)-amide (DALDA), the mu-opioid receptor agonist morphine, the mu/delta agonist D-Ala2, Leu5, Arg6-enkephalin (dalargin), the kappa-opioid receptor agonist spiradoline, and the sigma1-receptor antagonist DuP 734 on ventricular fibrillation threshold (VFT) was investigated in an experimental post-infarction cardiosclerosis model and an immobilization stress-induced model in rats. Both models produced a significant decrease in VFT. The postinfarction cardiosclerosis-induced decrease in VFT was 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 naloxone (0.2 mg/kg) completely eliminated the increase in cardiac electrical stability 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 post-infarction cardiosclerosis. This effect of spiradoline was blocked by nor-binaltorphimine. The immobilization stress-induced decrease in VFT was significantly reversed by administration of either DALDA, spiradoline or DuP 734. In conclusion, activation of either mu- or kappa1-opioid receptors or blockade of sigma1-receptors reversed the decrease in VFT in both cardiac compromised models. Since DALDA and dalargin essentially do not cross blood brain barriers, their effects on VFT may be mediated through peripheral mu-opioid receptors.

Topics: Animals; Anti-Arrhythmia Agents; beta-Endorphin; Disease Models, Animal; Dynorphins; Enkephalin, Leucine-2-Alanine; Heart; Immobilization; Ligands; Morphine; Myocardial Infarction; Myocardium; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Piperidines; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, delta; Stress, Physiological; Ventricular Fibrillation

The actions of opioid receptor agonists on stimulus evoked dopamine overflow in rat neostriatal slices were investigated using fast cyclic voltammetry. Activation of delta and mu receptors reversibly depressed striatal dopamine efflux induced by intrastriatal stimulation. The inhibitory effect of DADLE (D-Ala2, D-Leu5-enkephalin, delta/mu agonist), DPDPE (D-Pen2,5-enkephalin, delta selective) and DALDA (D-Arg2, Lys4-dermorphin-(1,4)-amide, mu selective), respectively, were concentration dependent and could be blocked by application of receptor subtype selective antagonists. At a concentration of 1 microM, the kappa receptor agonist U-50488H inhibited dopamine overflow. This effect could be partially antagonized by kappa receptor selective antagonists. Prior application of virtually ineffective concentrations (< or = 0.1 microM) of the kappa agonist reduced the efficacy of 1 microM U-50488H suggesting a desensitization of the receptor. Since the stimulus induced dopamine overflow in striatal slices can be attributed solely to the release of dopamine from presynaptic terminals, these experiments demonstrate that delta, mu and kappa opioid receptors exert an inhibitory control on striatal dopamine release via a presynaptic mechanism.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Dopamine; Dopamine Uptake Inhibitors; Electric Stimulation; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; In Vitro Techniques; Male; Neostriatum; Nomifensine; Oligopeptides; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu