Hemorphins, atypical endogenous opiate peptides, in sickle cell disease and their association with pain

Sickle cell disease (SCD) is a genetic disorder caused by a mutation in the beta hemoglobin gene, resulting in red blood cell (RBC) distortion, hemolysis, and severe pain episodes. Despite advancements in understanding acute crisis pain that is caused by vaso-occlusion, the neurobiological mechanisms underlying chronic pain in SCD remain poorly studied. Hemorphins, atypical endogenous opioid peptides derived from the hemoglobin beta chain in RBCs have analgesic effects and may contribute to SCD-related pain mechanisms, as their formation occurs when hemoglobin in RBCs is exposed to proteases in plasma. In this study, we investigated the levels of hemorphins in both plasma and nervous system of humanized transgenic SCD mice using liquid chromatography mass spectrometry. Our results show a significant elevation of hemorphins in SCD mice compared with wild-type controls, with a strong correlation with individual pain levels. These findings suggest that altered hemorphin processing in SCD may contribute to chronic pain by modulating the opioid signaling pathways, offering insights into the neurobiology of pain in SCD.