Supraspinal kappa-opioid receptors: new therapeutic strategies for pain, pruritus, and negative emotions

Research on kappa-opioid receptor (KOR) regulation of pain and itching has focused primarily on spinal and peripheral levels. However, the role of central KOR in this process, as well as the mechanisms exacerbating negative emotional responses to pain and itching, remains unknown. Therefore, this study aimed to utilize the advantages of intracerebroventricular (i.c.v.) administration of U50488H to explore supraspinal KOR activation on pain, itching, and negative emotions. U50488H, a prototypical KOR agonist, was administered i.c.v., with physiological saline as the control. The Hargreaves test and intradermal injection of histamine and chloroquine were conducted to assess thermal pain and itch behavior, respectively. The elevated plus maze (EPM), open field test (OFT), and tail suspension test (TST) were performed to evaluate negative emotions. i.c.v. administration of U50488H increased thermal pain latencies, reduced scratching behavior, and decreased locomotor activity in the central zone of the OFT and in the open arms of the EPM, while increasing immobility in the TST. i.c.v. pretreatment with the KOR antagonist nor-Binaltorphimine dihydrochloride reversed all of the above behaviors. In conclusion, central administration of U50488H can exhibit analgesic and antipruritic effects while also inducing negative emotional responses. Our results highlight the potential of supraspinal KOR as a promising therapeutic target in the combined treatment of pain, pruritus, and negative emotions.