kappaopioid

Kappa opioid receptor (KOR) is a G protein-coupled receptor that belongs to the opioid receptor family, along with mu and delta receptors. It is activated by endogenous dynorphins and by several synthetic ligands. KORs are distributed throughout the central nervous system and in peripheral tissues, with notable presence in brain regions involved in pain processing, emotion, and learning, as well as in the spinal cord dorsal horn where they contribute to analgesia.

Mechanism and pharmacology: KORs are coupled to Gi/Go proteins. Activation inhibits adenylyl cyclase, lowers cAMP levels, opens potassium channels, and closes voltage-gated calcium channels, reducing neuronal excitability and neurotransmitter release. This signaling underlies the receptor’s contributions to analgesia, particularly at the spinal level, and to modulating stress and mood. KORs can mediate dysphoria and psychotomimetic-like effects in humans, and may produce sedation and aversion, while also producing anti-pruritic effects in some contexts. Compared with mu-opioid receptor activation, KOR agonists generally show a lower risk of respiratory depression, though their adverse effects limit clinical use.

Endogenous ligands and pharmacology: The natural ligands are dynorphins. Exogenous selective KOR agonists include compounds such as U-50,488H and U-69,593, which have been used in research and development. Selective KOR antagonists, such as nor-binaltorphimine (nor-BNI), GNTI, and JDTic, are used in preclinical studies to explore KOR involvement in pain, mood, and substance use disorders.

Clinical status and research: KOR-targeted therapies have faced challenges due to undesirable side effects like dysphoria and mood disturbances. Nonetheless, research continues into whether KOR modulation can provide analgesia with lower abuse potential, or offer new approaches for mood disorders and addiction. The receptor was identified in the late 20th century, with dynorphin recognized as its endogenous ligand.