Mitigating morphine dependence and withdrawal: The role of venlafaxine and calcium channel blockers in mitochondrial damage and oxidative stress in the brain

Background

The reasons for morphine dependence and withdrawal symptoms are oxidative stress and dysfunction of cell mitochondria in the brain. Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), mitigates oxidative stress, while calcium channel blockers (nimodipine/diltiazem) prevent Ca²⁺-mediated mitochondrial dysfunction. In the present study, the effects of simultaneous administration of venlafaxine and calcium channel blockers on dependence and withdrawal syndrome of morphine and the role of mitochondrial damage and oxidative stress were assessed.

Methods

In this experimental study, the analgesic effect of venlafaxine, nimodipine, and diltiazem was investigated using the hot plate test to determine the optimal doses of drugs to use in subsequent experiments. To induce morphine dependence and withdrawal syndrome, male NMRI mice were treated with 50 mg/kg S.C. morphine for three consecutive days and 5 mg/kg S.C. morphine on the fourth day. 2 hours after the last dose of morphine, naloxone (5 mg/kg) was injected intraperitoneally, and the signs of jumping and standing were evaluated for 0.5 hours. Venlafaxine (20 mg/kg) alone or in combination with nimodipine (10 mg/kg) and diltiazem (40 mg/kg) was administered half an hour before morphine 50 mg/kg for three days. Brain slides were stained and examined under a light microscope. Brain mitochondria were isolated using a repeated centrifugation method to investigate mitochondrial oxidative stress. The dehydrogenase activity (MTT), membrane potential (MMP), ROS production rate, glutathione (GSH), and malondialdehyde (MDA) contents of the brain mitochondria were measured. The data were expressed as mean±standard deviation, and a p-value less than 0.05 was considered statistically significant.

Results

The administration of naloxone following repeated morphine injection increased withdrawal symptoms compared to the control group (morphine followed by solvent of naloxone) (P < 0.01). Administration of venlafaxine-nimodipine and venlafaxine-diltiazem before morphine reduced these symptoms compared to the morphine + naloxone group (P < 0.01). The injection of morphine followed by naloxone decreased MTT and GSH and increased MDA, MMP, and ROS compared to the control group (P < 0.01), and the injection of venlafaxine-nimodipine and venlafaxine-diltiazem half an hour before morphine reduced these alterations when compared to morphine + naloxone group (P < 0.05).

Conclusion

Coadministration of venlafaxine with calcium channel blockers could reduce morphine withdrawal symptoms and prevent its pathological damage. The suggested mechanism of this event is preventing mitochondrial damage and oxidative stress induced by morphine.