Morphine Enhances Doxorubicin-Induced Cardiotoxicity in the Rat

Abstract

Interventions to reduce the cardiotoxicity of doxorubicin are clinically relevant. Pharmacological preconditioning mimicking ischemic preconditioning has been demonstrated with morphine and represents an acceptable clinical intervention. The purpose of this study was to examine if pretreatment in vivo with morphine could reduce doxorubicin-induced cardiotoxicity ex vivo in a rat model. Wistar rats were divided into six groups and pretreated with an intraperitoneal (i.p.) injection of 3 or 10 mg/kg morphine, 1 mg/kg naloxone and saline, 1 mg/kg naloxone and 3 mg/kg morphine or saline, 60 min before excision of the heart. Biochemical indices such as troponin T (TnT) and hydrogen peroxide (H2O2) in effluate were measured together with physiological parameters in Langendorff hearts before and after doxorubicin infusion (2 mg/mL 0.05 mL/min for 45 min). Myocardial content of doxorubicin was measured at the end of infusion. Pretreatment with morphine, irrespective of dosage, produced a significant loss in left ventricular-developed pressure and an increase of TnT and H2O2 in effluate before doxorubicin infusion (p < 0.05). Morphine also produced a significant increase in left ventricular end-diastolic pressure and an increase of TnT and H2O2 in effluate (p < 0.05) at the end of doxorubicin infusion. Naloxone, a non-selective opioid receptor antagonist, abolished the effects of morphine both before and after doxorubicin infusion. Morphine, irrespective of dosage, increased myocardial content of doxorubicin compared to pretreatment with saline (p < 0.05). Pretreatment with morphine is associated with a cardiodepressive effect and enhances cardiotoxicity of doxorubicin measured by increased myocardial accumulation of doxorubicin and physiological and biochemical indices. The negative effects observed in our rat model are abolished by naloxone.

Cardiogenic shock induced by a high dose of intravenous morphine

“…The study reported that during the administration of doxorubicin, which has a cardiotoxic effect leading to the anthracyclineinduced cardiomyopathy, additional morphine administration aggravated the toxicity. The aggravating effect was not observed during an additional naloxone infusion, thus further supporting the claim [23]. This claim is especially important for patients suffering from neoplasia, who are often administered anthracycline-based chemotherapy alongside morphine-based analgesia.…”

A short review: Doxorubicin and its effect on cardiac proteins

“…44 Recent data on rodents utilizing drugs and inhibitors has proved to reverse the cardiac damage incurred by dox, and firmly supports troponin as an ultrasensitive positive footprint in dox-treated cancer models. Diazoxide, morphine, neuregulin, and aldose reductase inhibitors co-treated with Dox on rats in cardiac-plasma troponin levels is considered as an early prognostic indicator of dox-induced cardiotoxicity in breast cancer, colon cancer, and hematological cancer patients [45][46][47][48][49][50][51] (Table 2).…”

“…This action could be reversed in the presence of Ca 2+ chelators, indicating that a drop in intracellular cardiac Ca 2+ levels lowers the TnI phosphorylation. 45,47,48,51…”

“…Recent studies have demonstrated that a direct activation of PPAR by GW0742 ends in a higher phosphorylation of TnI and improves cardiac performance as well. This action could be reversed in the presence of Ca 2+ chelators, indicating that a drop in intracellular cardiac Ca 2+ levels lowers the TnI phosphorylation 45,47,48,51 …”

P-Glycoprotein/ABCB1 Might Contribute to Morphine/Cisplatin-Induced Hepatotoxicity in Rats

“…Animals were allocated into four groups (n = 10); control group, MOR-treated group receiving 10 mg/kg/day of MOR i.p. for 10 days [12], CP-treated group receiving a single i.p. of 7.5 mg/kg CP at day 5 of the experiment [13], and combined MOR/CP-treated group receiving both drugs as described.…”