Extracellular processing of proopiomelanocortin generates short beta endorphin that regulates rat keratinocytes via the delta opioid receptor.

Proopiomelanocortin (POMC), a precursor with multiple bioactive peptides, is expressed by keratinocytes and regulates various pathophysiological responses, including pruritus associated with atopic dermatitis (AD). In the skin, POMC is extracellularly processed into peptides like α-melanocyte-stimulating hormone (α-MSH); however, the processing and functional role of β-endorphin (β-END) remain unclear. Here, we investigated the molecular form and biological activity of β-END generated in the context of AD. We analyzed skin extracts from AD lesions using immunoprecipitation and MALDI-TOF MS, identifying β-END(1-9), a truncated peptide, as a major derivative. To explore opioid receptor expression in fetal rat skin keratinocytes (FRSK) using RT-PCR. Delta opioid receptor (DOR) was detected in FRSK cells. Functional assays showed β-END(1-9) reduced cAMP levels via DOR signaling, acting as a full agonist with about half the potency of methionine-enkephalin. To further explore its biological effects, DNA microarray analysis was conducted on β-END(1-9)-treated FRSK cells. Differential gene expression analysis revealed modulation of genes involved in collagen maturation and hyaluronic acid synthesis, suggesting roles in skin barrier function. Collectively, these findings suggest that POMC is processed into β-END(1-9) in atopic-inflammatory skin, and this peptide acts via DOR expressed in keratinocytes to promote the expression of skin-protective factors.