The Dynorphin/-Opioid Receptor System at the Interface of Hyperalgesia/Hyperkatifeia and Addiction

Abstract Purpose of Review Drug addiction is characterized by compulsive drug seeking and use, accompanied by negative emotional states (hyperkatifeia) and heightened pain sensitivity (hyperalgesia) during withdrawal. Both hyperalgesia and hyperkatifeia are integral components of substance use disorders, negatively impacting treatment and recovery. The underlying neurobiological mechanisms of hyperalgesia and hyperkatifeia involve alterations of brain reward and stress circuits, including the dynorphin/κ-opioid receptor (KOR) system. The dynorphin/KOR system modulates pain perception, negative affect, and addictive behaviors. Here, we review the preclinical evidence of dynorphin/KOR signaling in opioid withdrawal-induced hyperalgesia and hyperkatifeia. Recent Findings In opioid dependence models, pharmacological and genetic interventions of the dynorphin/KOR system attenuate somatic and motivational signs of withdrawal and addictive-like behaviors, highlighting its therapeutic potential. Understanding the intricate interplay between dynorphin/KOR signaling, hyperalgesia, hyperkatifeia, and addiction offers novel insights into treatment strategies for opioid use disorder and other substance use disorders. Summary Further research is needed to elucidate precise mechanisms of the sexual dimorphism of dynorphin/KOR signaling and identify targeted interventions to mitigate hyperalgesia and hyperkatifeia and facilitate recovery from addiction.