Effects of Lithium on Morphine Tolerance Using Analgesia, Nitrite Determination, Histology and Immunohistochemistry of Forehead Cortex in Adult Male Swiss Mice

Chronic use of opioids leads to analgesic tolerance. Protein kinase C (PKC), adenylyl cyclase (AC), nitric oxide (NO) and glycogen synthase kinase 3 beta (GSK-3β) are involved in morphine tolerance. Lithium activates the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway that inhibits GSK-3β and reduces morphine-induced tolerance. This study was performed to evaluate the effects of lithium on morphine dependence symptoms and tolerance of its analgesic effects in Swiss mice by GSK-3β signaling.

This experimental study was performed on 56 Swiss male albino mice that were randomly allocated into 8 groups (each containing 7 mice). The intraperitoneal injection of morphine at different concentrations (50, 50 and 75 mg/kg) and different hours (08:00, 11:00 and 16:00, respectively) was performed for 4 days, and a single dose 50 mg/kg was administered on the 5th day. The effects of three doses of lithium (1, 5 and 10 mg/kg) given orally, 45 min before morphine injections on morphine-induced analgesic tolerance were evaluated. To evaluate analgesia latency on day 1, 3 and 5, tail flick and hot plate tests were done. The brain of each animal was removed to measure nitrite levels, and histological evaluation and immunohistochemistry for p-glycogen synthase (p-GSSer640) were performed on the last day of the study.

Co-administration of lithium significantly increased the latency of analgesia in comparison with the morphine group on the 3rd and 5th day (P<0.05). Lithium reduced the morphine-induced increase of nitrite levels and also reduced brain damage. In addition, immunohistochemistry assay of p-GSSer640 indicated a significant reduction of the morphine-induced phosphorylation of GS at S640 by GSK in the lithium-treated mice.

Lithium administration can reduce morphine tolerance in adult male Swiss mice.