Peripheral κ opioid receptor in pain and inflammation: From molecular signalling and gene expression to drug discovery

The κ opioid receptor (κ receptor, KOR) is a G protein‐coupled receptor with well established roles in analgesia and immune modulation. Although historically studied primarily in the central nervous system (CNS), growing evidence indicates that κ signalling in peripheral tissues plays an important role in regulating pain, inflammation and immune responses. Targeting peripheral κ receptor represents an attractive therapeutic strategy to achieve analgesic and anti‐inflammatory effects while minimising CNS‐mediated adverse effects associated with classical opioid therapies. Recent advances have shown that κ receptor function is not only shaped by ligand‐dependent and pathway‐selective signalling but also by pronounced differences in receptor expression across tissues and disease states. These insights have expanded the relevance of the κ receptor beyond nociception to a broader range of pathological conditions, including peripheral pain and inflammatory or autoimmune diseases. In this review, we summarise current knowledge on peripheral κ receptor biology, integrating molecular signalling mechanisms with emerging data on tissue‐specific receptor expression and disease‐associated regulation. We discuss the role of κ receptors in peripheral pain and inflammatory diseases, such as arthritis, inflammatory bowel disease and psoriasis, highlighting how altered receptor signalling contributes to disease pathophysiology. In addition, we examine genetic variants in the OPRK1 gene and its potential implications for receptor function and pharmacological responses. Finally, we review current and emerging drug discovery strategies targeting peripheral κ receptors, with particular emphasis on peptide‐based ligands and innovative molecular design approaches. Together, these developments position peripheral κ receptors as a promising and versatile therapeutic target for the treatment of pain and inflammatory diseases.