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.