Abstract
Antipruritic effects of kappa opioid receptor (KOR) agonists have been shown in rodent models of acute and chronic scratching (itchlike behavior). Three KOR agonists, nalfurafine, difelikefalin, and nalbuphine, are in clinical studies for antipruritic effects in chronic itch of systemic and skin diseases. Nalfurafine (in Japan) and difelikefalin (in the USA) were approved to be used in the treatment of chronic itch in hemodialysis patients. The FDA-approved nalbuphine has been used in clinic for over 40 years, and it is the only narcotic agonist that is not scheduled. We aimed to study (a) antiscratch activity of nalbuphine against TAT-HIV-1 protein (controls HIV transcription)-, deoxycholic acid (DCA, bile acid)-, and chloroquine (CQ)-induced scratching in a mouse model of acute itch; and (b) whether the effect of nalbuphine is produced via KORs. First, dose–responses were developed for pruritogens. Mice were pretreated with nalbuphine (0.3–10 mg/kg) and then a submaximal dose of pruritogens were administered and the number of scratching bouts was counted. To study if the antiscratch effect of nalbuphine is produced via KOR, we used KOR knock out mice and pharmacologic inhibition of KORs using nor-binaltorphimine, a KOR antagonist. For this aim, we used CQ as a pruritogen. We found that: (a) TAT-HIV-1 protein elicits scratching in a dose-dependent manner; (b) nalbuphine inhibits scratching induced by TAT-HIV-1, DCA, and CQ dose-dependently; and (c) nalbuphine inhibits scratching induced by CQ through KORs. In conclusion, nalbuphine inhibits scratching elicited by multiple pruritogens.
Highlights
As of today, three kappa opioid receptor (KOR) agonists, nalfurafine (TRK-820, Remich®), difelikefalin (CR845, KorsuvaTM), and nalbuphine (HaduvioTM, KOR agonist and a weak mu opioid receptor partial agonist) (Figure 1) are in clinical studies for treating chronic itch of chronic kidney disease, cholestatic liver disease, and atopic dermatitis [1,2,3,4]
Nalfurafine was approved in Japan and recently, difelikefalin was approved by the FDA in the USA for the treatment of chronic itch in hemodialysis patients
We had shown previously that nalfurafine inhibits scratch3inogf 11 induced by CQ [29], so lastly, we studied whether nalbuphine, like nalfurafine, would inhibit scratching in mice
Summary
Three kappa opioid receptor (KOR) agonists, nalfurafine (TRK-820, Remich®), difelikefalin (CR845, KorsuvaTM), and nalbuphine (HaduvioTM, KOR agonist and a weak mu opioid receptor partial agonist) (Figure 1) are in clinical studies for treating chronic itch of chronic kidney disease, cholestatic liver disease, and atopic dermatitis [1,2,3,4]. Nalbuphine is effective to reduce the itch like behavior induced by the TAT-HIV-1 protein (a protein is responsible for transcription of viruses and infection), DCA (one of the mediators responsible for cholestatic pruritus), and CQ in mice model acute itch. Since all these three conditions cause clinical itch in humans, we suggest that nalbuphine, a drug that has been in clinical use for over 40 years and is not a scheduled agent, will be effective for treating chronic itch in humans. Nalbuphine is already in clinical studies for cholestasis, but a clinical trial for chronic itch in HIV patients could be added
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