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Opioid receptor independent effects of morphine on membrane currents in single cardiac myocytes
1Department of Pharmacology, College of Medicine, National Taiwan University, Taipei.
Abstract:
We have examined the effects of morphine, a mu-opioid receptor agonist, on various membrane ionic currents in rat ventricular and human atrial myocytes, using patch-clamp techniques in the whole-cell configuration. Morphine produced a concentration-dependent reduction in peak transient sodium current. When the sodium current (INa) was evoked at 5-s intervals the estimated IC50 for morphine was approximately 30 mumol litre-1. Morphine 10 mumol litre-1 inhibited INa with a 5-mV shift in the potential-dependent inactivation curve to negative potentials and retarded the INa recovery rate from the inactivated state. Use-dependent INa block was not observed when INa was elicited at frequencies varying from 0.2 to 20 Hz. Morphine did not significantly affect the inward calcium current (ICa), transient outward current (Ito) or the inwardly rectifying potassium current (IK1) at a concentration of 30 mumol litre-1. The inhibitory effect of morphine on INa could not be prevented or reversed by treatment with the opioid antagonist naloxone. Therefore, we suggest that morphine can directly inhibit the Na+ inward current and bind to inactivated Na+ channels.
Insights
Morphine directly inhibits sodium channels (INa) in heart cells, affecting cardiac function. This effect on INa is concentration-dependent and not blocked by naloxone, suggesting a direct interaction with the channel.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Morphine, a potent opioid analgesic, interacts with mu-opioid receptors.
- Understanding morphine's non-analgesic effects on cardiac ion channels is crucial for patient safety.
Purpose of the Study:
- To investigate the direct effects of morphine on cardiac ionic currents.
- To determine the specific ion channels affected by morphine in cardiac myocytes.
Main Methods:
- Whole-cell patch-clamp technique applied to rat ventricular and human atrial myocytes.
- Concentration-response analysis of morphine's effect on various ionic currents.
- Assessment of naloxone's ability to block morphine's effects.
Main Results:
- Morphine caused a concentration-dependent reduction in peak transient sodium current (INa), with an IC50 of approximately 30 µmol/L.
- Low concentrations of morphine (10 µmol/L) shifted the INa inactivation curve and slowed recovery from inactivation.
- No significant effects of morphine were observed on calcium current (ICa), transient outward potassium current (Ito), or inwardly rectifying potassium current (IK1).
- Naloxone did not prevent or reverse the inhibitory effects of morphine on INa.
Conclusions:
- Morphine directly inhibits cardiac sodium channels (INa).
- The findings suggest morphine binds to inactivated sodium channels.
- These direct effects on INa are independent of mu-opioid receptor antagonism.