Opioids regulate the functional state of immune cells and reduce inflammatory cardiac injury: Role of opioid receptors, MRGPRX2, and TLR4

Neutrophils, macrophages, CD3⁺, CD4⁺, and CD8⁺ T-lymphocytes express µ-, δ-, and κ-opioid receptors (ORs) with both high and low affinities for opioids. Mast cells express the atypical OR mas-related G-protein-coupled receptor X2 (MRGPRX2), which has a low affinity for morphine. Neutrophils and macrophages synthesize and release opioid peptides. The activation of ORs increases the synthesis of proinflammatory cytokines and the production of reactive oxygen species (ROS) in unstimulated leukocytes. Conversely, the activation of ORs reduces proinflammatory cytokine synthesis in stimulated neutrophils and macrophages. Morphine inhibits Toll-like receptor 4 (TLR4) expression in macrophages, thereby reducing inflammation. Methadone induces ROS production in mast cells through the activation of TLR4. Stimulation of TLR4 induces β-endorphin synthesis in macrophages. The production of pro-inflammatory cytokines and ROS contributes to cardiac reperfusion injury. The activation of κ₁- and µ-ORs reduces pro-inflammatory cytokine production by leukocytes and suppresses inflammatory injury to the heart and other organs.