Lithium reverses mechanical allodynia through a mu opioid-dependent mechanism

BACKGROUND: Lithium is widely used to treat bipolar disorders and displays mood stabilizing properties. In addition, lithium relieves painful cluster headaches and has a strong analgesic effect in neuropathic pain rat models. OBJECTIVES: To investigate the analgesic effect of lithium on the cuff model of neuropathic pain. METHODS: We used behavioral and pharmacological approaches to study the analgesic effect of a single injection of lithium in wild-type and mu opioid receptor (MOR) null cuffed neuropathic mice. Mass spectrometry and enzyme-linked immunosorbent assay allowed to measure the levels of endogenous MOR agonist beta-endorphin as well as monoamines in brain and plasma samples 4 h after lithium administration. RESULTS: A single injection of lithium chloride (100 mg/kg, ip) alleviated mechanical allodynia for 24 h, and this effect was absent in MOR null neuropathic mice. Biochemical analyses highlight a significant increase in beta-endorphin levels by 30% in the brain of lithium-treated mice compared to controls. No variation of beta-endorphin was detected in the blood. CONCLUSIONS: Together, our results provide evidence that lithium induces a long-lasting analgesia in neuropathic mice presumably through elevated brain levels of beta-endorphin and the activation of MORs.