Kappa Opioid Receptor
One of the three main opioid receptor subtypes, found primarily in the spinal cord, brain, and peripheral tissues. Activation of kappa receptors produces analgesia and antipruritic (anti-itch) effects without the euphoria or addiction potential associated with mu opioid receptors. Difelikefalin selectively targets this receptor.
Technical Context
KOR activation in the periphery produces analgesia and antipruritic (anti-itch) effects. In the CNS, KOR activation produces dysphoria (opposite of euphoria) and sedation — which is why CNS-penetrant KOR agonists have poor tolerability. Difelikefalin was deliberately designed as a peripherally restricted KOR agonist, with physicochemical properties (high polarity, low lipophilicity, D-amino acid incorporation) preventing BBB penetration. It achieves therapeutic antipruritic effects in CKD patients on haemodialysis by activating peripheral KOR without central side effects. This design strategy demonstrates how understanding receptor distribution and BBB pharmacology enables targeted peptide drug design.