The effect of various morphine weaning regimens on the sequelae of opioid tolerance involving physical dependency, anxiety and hippocampus cell neurodegeneration in rats

Abstract

Chronic consumption of morphine induces physical dependency, anxiety, and neurodegeneration. In this study, morphine on its own has been used for the management of morphine‐induced dependency, oxidative stress, and apoptosis. Forty‐eight male rats were randomly divided into six groups. Rats in groups 1–5 were made morphine dependent by an increasing manner of morphine for 7 days (15–45 mg/kg). For the next 14 days, morphine was administered using the following regimen: (i) once daily 45 mg/kg (positive controls), (ii) the same dose at additional intervals (6 h longer than the previous intervals each time), (iii) 45 mg/kg of morphine at irregular intervals like of 12, 24, 36 h, (iv) decreasing dose once daily (every time 2.5 mg/kg less than the former dosage). Group 5 received 45 mg/kg of morphine and 10 mg/kg of SOD mimetic agent (M40401) injection per day. Group 6 (negative control) received saline solution only. On day 22, all animals received naloxone (3 mg/kg) and their Total Withdrawal Index (TWI) and blood cortisol levels were measured. After drug treatment, hippocampus cells were isolated, and oxidative, antioxidative, and apoptotic factors were evaluated. Various regimens of morphine reduced TWI, cortisol levels, Bax activity, caspase‐3, caspase‐9, TNF‐α, and IL‐1β and lipid peroxidation. In all treatment groups, GSH level, superoxide dismutase, glutathione peroxidase, and Bcl‐2 activity were significantly increased. Furthermore, SOD mimetic agent c diminished morphine effect on SOD activity. Thus, varying the dosage regimen of morphine can reduce the severity of morphine‐induced dependency and neurodegeneration.