¬EGFR interaction with MOR and NMDAR in oral cancer pain and morphine analgesia tolerance

EGFR signaling is increased in the oral tumor microenvironment compared to normal oral tissues in patients. In a clinical trial where patients were treated with either Erlotinib or placebo in addition to chemotherapy, Erlotinib reduced chemotherapy-induced adverse effects related to pain. RNA-sequencing of the tumor revealed alterations in pain-related genes following Erlotinib, with altered pathways such as neurotransmitter uptake and metabolism in glial cells, IL-10, neuroinflammation, and neurovascular coupling. EGFR inhibitors reduced SC activation in vitro. In mouse models of oral cancer, EGFR inhibitors reduced pain and morphine tolerance. Mechanistically, EGFR ligands such as HB-EGF and TGFalpha suppress DAMGO-induced cAMP production, and internalize MOR to endosomes, resulting in MOR desensitization in an EGFR-dependent manner. Treatment with HB-EGF or TGFalpha augmented presynaptic and postsynaptic NMDAR activity of substantia gelatinosa neurons in the TNc.