Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch

Kappa opioid receptor (KOR) agonists have been promising therapeutic candidates, owing to their potential for relieving pain and treating intractable pruritus. Although lacking morphine-like central nervous system (CNS) effects, KOR agonists do elicit sedation, dysphoria and diuresis which seriously...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Xin Wang, Xiaoli Gou, Xiaojuan Yu, Dongdong Bai, Bowei Tan, Pingfeng Cao, Meilin Qian, Xiaoxiao Zheng, Hairong Wang, Pingming Tang, Chen Zhang, Fei Ye, Jia Ni
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	HSK21542 kappa opioid receptor pain pruritus animal models Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/1887529fd32b4df59dbadda726d129cb
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1887529fd32b4df59dbadda726d129cb
record_format	dspace
spelling	oai:doaj.org-article:1887529fd32b4df59dbadda726d129cb2021-11-16T05:18:12ZAntinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch1663-981210.3389/fphar.2021.773204https://doaj.org/article/1887529fd32b4df59dbadda726d129cb2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.773204/fullhttps://doaj.org/toc/1663-9812Kappa opioid receptor (KOR) agonists have been promising therapeutic candidates, owing to their potential for relieving pain and treating intractable pruritus. Although lacking morphine-like central nervous system (CNS) effects, KOR agonists do elicit sedation, dysphoria and diuresis which seriously impede their development. Peripherally-restricted KOR agonists have a poor ability to penetrate into the CNS system, so that CNS-related adverse effects can be ameliorated or even abolished. However, the only approved peripherally-restricted KOR agonist CR845 remains some frequent CNS adverse events. In the present study, we aim to address pharmacological profiles of HSK21542, with an expectation to provide a safe and effective alternative for patients who are suffering from pain and pruritus. The in vitro experimental results showed that HSK21542 was a selective and potent KOR agonist with higher potency than CR845, and had a brain/plasma concentration ratio of 0.001, indicating its peripheral selectivity. In animal models of pain, HSK21542 significantly inhibited acetic acid-, hindpaw incision- or chronic constriction injury-induced pain-related behaviors, and the efficacy was comparable to CR845 at 15 min post-dosing. HSK21542 had a long-lasting analgesic potency with a median effective dose of 1.48 mg/kg at 24 h post-drug in writhing test. Meanwhile, the antinociceptive activity of HSK21542 was effectively reversed by a KOR antagonist nor-binaltorphimine. In addition, HSK21542 had powerful antipruritic activities in compound 48/80-induced itch model. On the other hand, HSK21542 had a weak ability to produce central antinociceptive effects in a hot-plate test and fewer effects on the locomotor activity of mice. HSK21542 didn’t affect the respiratory rate of mice. Therefore, HSK21542 might be a safe and effective KOR agonist and promising candidate for treating pain and pruritus.Xin WangXiaoli GouXiaojuan YuDongdong BaiBowei TanPingfeng CaoMeilin QianXiaoxiao ZhengHairong WangPingming TangChen ZhangFei YeJia NiFrontiers Media S.A.articleHSK21542kappa opioid receptorpainpruritusanimal modelsTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	HSK21542 kappa opioid receptor pain pruritus animal models Therapeutics. Pharmacology RM1-950
spellingShingle	HSK21542 kappa opioid receptor pain pruritus animal models Therapeutics. Pharmacology RM1-950 Xin Wang Xiaoli Gou Xiaojuan Yu Dongdong Bai Bowei Tan Pingfeng Cao Meilin Qian Xiaoxiao Zheng Hairong Wang Pingming Tang Chen Zhang Fei Ye Jia Ni Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch
description	Kappa opioid receptor (KOR) agonists have been promising therapeutic candidates, owing to their potential for relieving pain and treating intractable pruritus. Although lacking morphine-like central nervous system (CNS) effects, KOR agonists do elicit sedation, dysphoria and diuresis which seriously impede their development. Peripherally-restricted KOR agonists have a poor ability to penetrate into the CNS system, so that CNS-related adverse effects can be ameliorated or even abolished. However, the only approved peripherally-restricted KOR agonist CR845 remains some frequent CNS adverse events. In the present study, we aim to address pharmacological profiles of HSK21542, with an expectation to provide a safe and effective alternative for patients who are suffering from pain and pruritus. The in vitro experimental results showed that HSK21542 was a selective and potent KOR agonist with higher potency than CR845, and had a brain/plasma concentration ratio of 0.001, indicating its peripheral selectivity. In animal models of pain, HSK21542 significantly inhibited acetic acid-, hindpaw incision- or chronic constriction injury-induced pain-related behaviors, and the efficacy was comparable to CR845 at 15 min post-dosing. HSK21542 had a long-lasting analgesic potency with a median effective dose of 1.48 mg/kg at 24 h post-drug in writhing test. Meanwhile, the antinociceptive activity of HSK21542 was effectively reversed by a KOR antagonist nor-binaltorphimine. In addition, HSK21542 had powerful antipruritic activities in compound 48/80-induced itch model. On the other hand, HSK21542 had a weak ability to produce central antinociceptive effects in a hot-plate test and fewer effects on the locomotor activity of mice. HSK21542 didn’t affect the respiratory rate of mice. Therefore, HSK21542 might be a safe and effective KOR agonist and promising candidate for treating pain and pruritus.
format	article
author	Xin Wang Xiaoli Gou Xiaojuan Yu Dongdong Bai Bowei Tan Pingfeng Cao Meilin Qian Xiaoxiao Zheng Hairong Wang Pingming Tang Chen Zhang Fei Ye Jia Ni
author_facet	Xin Wang Xiaoli Gou Xiaojuan Yu Dongdong Bai Bowei Tan Pingfeng Cao Meilin Qian Xiaoxiao Zheng Hairong Wang Pingming Tang Chen Zhang Fei Ye Jia Ni
author_sort	Xin Wang
title	Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch
title_short	Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch
title_full	Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch
title_fullStr	Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch
title_full_unstemmed	Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch
title_sort	antinociceptive and antipruritic effects of hsk21542, a peripherally-restricted kappa opioid receptor agonist, in animal models of pain and itch
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/1887529fd32b4df59dbadda726d129cb
work_keys_str_mv	AT xinwang antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch AT xiaoligou antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch AT xiaojuanyu antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch AT dongdongbai antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch AT boweitan antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch AT pingfengcao antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch AT meilinqian antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch AT xiaoxiaozheng antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch AT hairongwang antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch AT pingmingtang antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch AT chenzhang antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch AT feiye antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch AT jiani antinociceptiveandantipruriticeffectsofhsk21542aperipherallyrestrictedkappaopioidreceptoragonistinanimalmodelsofpainanditch
_version_	1718426651211071488

Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch

Ejemplares similares