Distinct Components of Morphine Effects on Cardiac Myocytes are Mediated by the κ and δ Opioid Receptors

Morphine exerts direct effects on cultured cardiac myocytes from neonatal rats. These effects are mediated via theδand theκopioid receptors, asμopioid receptors are not present in neonatal cardiomyocyte cultures. Binding parameters to theδandκopioid receptors were determined in membrane preparations from these cultures by heterologous competition to [3H]diprenorphine binding, with [D-Pen2, D-Pen5]-enkephalin (DPDPE) andtrans-(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 theδor theκopioid receptor alone, cardiac myocytes were exposed to morphine in the presence of specific antagonists to theκorδopioid receptor respectively. Activation of theκopioid 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 theδopioid 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 theδopioid but not through theκopioid receptors were pertussis toxin sensitive, indicating coupling of theδopioid 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.