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 varying 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 can synthesize and release endogenous opioid peptides. Activation of ORs enhances the synthesis of proinflammatory cytokines and the production of reactive oxygen species (ROS) in unstimulated leukocytes. Conversely, OR activation reduces proinflammatory cytokine synthesis in stimulated neutrophils and macrophages. Morphine inhibits Toll-like receptor 4 (TLR4) expression in macrophages, thereby attenuating inflammation, whereas methadone induces ROS production in mast cells through TLR4 activation. Stimulation of TLR4 triggers β-endorphin synthesis in macrophages. The production of proinflammatory cytokines and ROS contributes to cardiac reperfusion injury. Importantly, activation of κ ₁- and µ-ORs suppresses proinflammatory cytokine production by leukocytes, thereby mitigating inflammatory injury to the heart and other organs.