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 the δ and the κ opioid receptors, as μ opioid receptors are not present in neonatal cardiomyocyte cultures. Binding parameters to the δ and κ 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 δ or the κ opioid receptor alone, cardiac myocytes were exposed to morphine in the presence of specific antagonists to the κ or δ opioid receptor respectively. Activation of the κ 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 δ 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⁺] transients. The effects mediated through the δ opioid but not through the κ opioid receptors were pertussis toxin sensitive, indicating coupling of the δ 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.