Interleukin-4 (IL-4) is an anti-inflammatory cytokine, which can be protective in inflammatory and neurological disorders, and can alleviate pain. Classically, IL-4 diminishes pain by blocking the production of pro-inflammatory cytokines. Here, we uncovered that IL-4 induces acute antinociception by IL-4 receptor α (IL-4Rα)-dependent release of opioid peptides from M1 macrophages at injured nerves. As a model of pathological pain we used a chronic constriction injury (CCI) of the sciatic nerve in male mice. A single application of IL-4 at the injured nerves (14 days following CCI) attenuated mechanical hypersensitivity evaluated by von Frey filaments, which was reversed by co-injected antibody to IL-4Rα, antibodies to opioid peptides such as Met-enkephalin (ENK), β-endorphin and dynorphin A 1-17, and selective antagonists of δ-, µ- and κ-opioid receptors. Injured nerves were predominately infiltrated by pro-inflammatory M1 macrophages and IL-4 did not change their numbers or the phenotype, assessed by flow...