Antiarrhythmic effect of prolonged morphine exposure is accompanied by altered myocardial adenylyl cyclase signaling in rats.
BACKGROUND
Morphine is often administered to patients for pain management, but it is also recommended to ameliorate some types of cardiovascular diseases. Nevertheless, there is a lack of information regarding the effect of prolonged morphine treatment on myocardial adenylyl cyclase (AC) signaling, which plays an important role in regulating heart function.


METHODS
The present work has investigated the consequences of 10-day administration of high morphine doses (10 mg/kg per day) to adult Wistar rats for functioning of the G-protein-mediated AC signaling system.


RESULTS
Morphine treatment appreciably affected neither the number of myocardial β-adrenoceptors nor the content of selected subunits of trimeric G-proteins (G(s)α, G(i/o)α, G(z)α, G(q/11)α and Gβ) but the amount of the dominant myocardial AC isoform V/VI almost doubled. These alterations were accompanied by a marked AC supersensitization: the enzyme activity stimulated by manganese, fluoride, forskolin or isoproterenol was considerably increased (by about 50-100%). In contrast, the ability of opioid agonists to inhibit forskolin-stimulated AC activity was slightly but significantly decreased in both groups. Besides that, morphine markedly decreased the incidence of ischemic ventricular arrhythmias induced by coronary artery occlusion, but did not significantly influence infarct size and arrhythmias occurring during reperfusion.


CONCLUSIONS
Overall, these results indicate that prolonged treatment of rats with high doses of morphine substantially alters the function of myocardial G-protein-regulated AC signaling. These alterations are accompanied by a reduced susceptibility to ischemia-induced ventricular arrhythmias.
Department of Physiology, Faculty of Science, Charles University in Prague, Vinicna 7, 128 44 Prague, Czech Republic.
Jitka
J
Skrabalova
Jan
J
Neckar
Lucie
L
Hejnova
Iveta
I
Bartonova
Frantisek
F
Kolar
Jiri
J
Novotny
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000201:enzymology / Q000517:prevention & control; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D011943:Receptors, Adrenergic, beta; D009020:Morphine; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases