Peripheral κ Opioid Receptor Emerges as Versatile Target for Pain and Inflammatory Diseases, Highlighting Peptide Ligands

Classical opioid therapies, while effective for pain, carry significant risks of CNS-mediated adverse effects, including addiction, tolerance, and respiratory depression. This necessitates the development of novel analgesic and anti-inflammatory strategies that can achieve therapeutic benefits without these systemic drawbacks. The κ opioid receptor (KOR), a G protein-coupled receptor, has established roles in both analgesia and immune modulation. Historically, research focused on its central nervous system (CNS) functions. However, a growing body of evidence now points to the critical role of KOR signaling in peripheral tissues for regulating pain, inflammation, and immune responses, presenting a compelling opportunity to develop safer, targeted therapeutics.

This comprehensive review synthesized current knowledge on peripheral κ opioid receptor (KOR) biology, integrating molecular signaling mechanisms with emerging data on tissue-specific receptor expression and disease-associated regulation. The authors discussed KORs' role in peripheral pain and inflammatory diseases like arthritis, inflammatory bowel disease (IBD), and psoriasis, analyzing how altered signaling contributes to pathophysiology. The review also examined genetic variants in the OPRK1 gene and their implications for receptor function and pharmacological responses. Finally, it explored current and emerging drug discovery strategies targeting peripheral KORs, with emphasis on peptide-based ligands and innovative molecular design.

The review highlights that peripheral κ opioid receptors (KORs) are crucial regulators of pain, inflammation, and immune responses, offering a therapeutic avenue to achieve analgesic and anti-inflammatory effects while minimizing CNS-mediated adverse effects associated with classical opioid therapies. KOR function is not solely determined by ligand-dependent and pathway-selective signaling but also by significant differences in receptor expression across various tissues and disease states. These insights expand KOR's relevance beyond nociception to a broader range of pathological conditions.

KORs play a significant role in the pathophysiology of inflammatory diseases such as arthritis, inflammatory bowel disease, and psoriasis, where altered receptor signaling contributes to disease progression.

Genetic variants in the OPRK1 gene were identified as potentially influencing KOR function and individual pharmacological responses. The review also underscored the growing focus on peptide-based ligands and innovative molecular design as promising strategies for developing new drugs specifically targeting peripheral KORs.