Dissociable effects of the kappa opioid receptor agonist nalfurafine on pain/itch-stimulated and pain/itch-depressed behaviors in male rats

Rationale Nalfurafine is a G protein signaling-biased kappa opioid receptor (KOR) agonist approved in Japan for second-line treatment of uremic pruritus. Neither nalfurafine nor any other KOR agonist is currently approved anywhere for treatment of pain, but recent evidence suggests that G protein signaling-biased KOR agonists may have promise as candidate analgesics/antipruritics with reduced side effects compared to nonbiased or ß-arrestin-signaling-biased KOR agonists. Objectives This study compared nalfurafine effects in rats using assays of pain-stimulated and pain-depressed behavior used previously to evaluate other candidate analgesics. Nalfurafine effects were also examined in complementary assays of itch-stimulated and itch-depressed behavior. Methods Intraperitoneal lactic acid (IP acid) and intradermal serotonin (ID 5HT) served as noxious and pruritic stimuli, respectively, in male Sprague Dawley rats to stimulate stretching (IP acid) or scratching (ID 5HT) or to depress positively reinforced operant responding in an assay of intracranial self-stimulation (ICSS; both stimuli). Results Nalfurafine was equipotent to decrease IP acid-stimulated stretching and ID 5HT-stimulated scratching; however, doses of nalfurafine that decreased these pain/itch-stimulated behaviors also decreased control ICSS performance. Moreover, nalfurafine failed to alleviate either IP acid- or ID 5HT-induced depression of ICSS. Conclusions These results suggest that nalfurafine-induced decreases in pain/itch-stimulated behaviors may reflect nonselective decreases in motivated behavior rather than analgesia or antipruritus against the noxious and pruritic stimuli used here. This conclusion agrees with the absence of clinical data for nalfurafine analgesia and the weak clinical data for nalfurafine antipruritus. Nalfurafine bias for G protein signaling may not be sufficient for clinically safe and reliable analgesia or antipruritus.