Distinct components of morphine effects on cardiac myocytes are mediated by the kappa and delta opioid receptors.
Morphine exerts direct effects on cultured cardiac myocytes from neonatal rats. These effects are mediated via the delta and the kappa opioid receptors, as mu opioid receptors are not present in neonatal cardiomyocyte cultures. Binding parameters to the delta and kappa opioid receptors were determined in membrane preparations from these cultures by heterologous competition to [3H]diprenorphine binding, with [D-Pen2, D-Pen5]-enkephalin (DPDPE) and trans-(dl)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulfonate (U-50,488H) as specific displacers respectively. To define the components of morphine effects mediated via activation of either the delta or the kappa opioid receptor alone, cardiac myocytes were exposed to morphine in the presence of specific antagonists to the kappa or delta opioid receptor respectively. Activation of the kappa opioid receptors by morphine caused a transient increase in Ca2+ influx, leading to increase in amplitudes of [Ca2+]i transients and contraction, with no change in the intracellular pH. Activation of the delta opioid receptors alone by morphine caused a decrease in the amplitude of contraction. This decrease was mediated by a decrease in the intracellular pH leading to reduced responsiveness of the myofilaments to Ca2+. There was no change in Ca2+ influx and in the amplitude of [Ca2+]i transients. The effects mediated through the delta opioid but not through the kappa opioid receptors were pertussis toxin sensitive, indicating coupling of the delta opioid receptors to pertussis toxin sensitive GTP-binding proteins. The overall effects of morphine on the neonatal cardiac myocytes were the sum of the effects exerted by morphine when it activated each of the opioid receptors alone.
Ela
C
C
Department of Bacteriology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Barg
J
J
Vogel
Z
Z
Hasin
Y
Y
Eilam
Y
Y
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D009020:Morphine / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017465:Receptors, Opioid, delta / Q000187:drug effects* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000378:metabolism
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D009020:Morphine; C055382:naltrindole; D002118:Calcium