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. 2021 Nov 16:12:773204.
doi: 10.3389/fphar.2021.773204. eCollection 2021.

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

Xin Wang  1 , Xiaoli Gou  2 , Xiaojuan Yu  2 , Dongdong Bai  2 , Bowei Tan  2 , Pingfeng Cao  2 , Meilin Qian  2 , Xiaoxiao Zheng  2 , Hairong Wang  2 , Pingming Tang  2 , Chen Zhang  2 , Fei Ye  2 , Jia Ni  2
Affiliations

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

Xin Wang et al. Front Pharmacol. .

Abstract

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.

Keywords: HSK21542; animal models; kappa opioid receptor; pain; pruritus.

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Conflict of interest statement

Authors XG, XY, DB, BT, PC, MQ, XZ, HW, PT, CZ, FY, and JN are employed by Haisco Pharmaceutical Group Co., Ltd. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Chemical structures of HSK21542 (A) and CR845 (B).
FIGURE 2
FIGURE 2
Kappa opioid receptor binding affinity and the effects on forskolin-induced cAMP accumulation of HSK21542 and CR845. (A) Concentration-effect curves of the inhibitory rates induced by HSK21542, CR845 or U69593 (the positive control) on [3H]diprenorphine binding to KOR. (B) The binding kinetic curves of HSK21542 binding to KOR. (C) The binding kinetic curves of CR845 binding to KOR. (D) Concentration-effect curves of the inhibitory rates induced by HSK21542, CR845 or U69593 (the positive control) on forskolin-induced cAMP accumulation. Data are presented as means ± SD of triple determinations.
FIGURE 3
FIGURE 3
Antinociceptive effects of HSK21542 and CR845 in acetic acid-induced writhing response in mice. (A) The writhing tests were conducted at 15 min post-dosing. (B) Nor-binaltorphimine (Nor-BNI, 32 mg/kg, s.c.), a KOR antagonist, was given at 24 h before drug administration, and the antinociceptive effects of HSK21542 and CR845 were examined at 15 min post-dosing. (C) The writhing tests were performed at 24 h post-dosing. Data are presented as means ± SD (n = 10/group). (A, C) *p < 0.05, ***p < 0.001 vs. vehicle, one-way ANOVA followed by Dunnett’s test; (B) ***p < 0.001 vs. vehicle, Student’s t-test; ### p < 0.001 vs. vehicle, Mann-Whitney test. V, Vehicle; M, Morphine (10 mg/kg, a positive control).
FIGURE 4
FIGURE 4
Antiallodynic effects of HSK21542 and CR845 in hindpaw incision- or CCI-induced mechanical pain. In hindpaw incision model, the mechanical allodynia testing (von Frey) was performed at 15 min (A) and 24 h (B) after drug administration. In CCI model, mechanical allodynia testing was performed at 0.25, 2, 6, 12 and 24 h post-drug (C, E), and the area under the curve (AUC) was calculated using a trapezoidal method (D, F). Morphine was presented as a positive control. Data are presented as means ± SD (n = 7–10/group). (A and B) *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle, Kruskal-Wallis test followed by Dunn’s post-hoc test; (C, E) *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle, two-way ANOVA followed by Dunnett’s test; (D, F) *p < 0.05, ***p < 0.001 vs. vehicle, one-way ANOVA followed by Dunnett’s test; ### p < 0.05 vs. vehicle, Mann-Whitney test. V, Vehicle.
FIGURE 5
FIGURE 5
Antipruritic effects of HSK21542 and CR845 in compound 48/80-induced itch model. Data are presented as means ± SD (n = 10/group). *p < 0.05, ***p < 0.001 vs. vehicle, one-way ANOVA followed by Dunnett’s test; ### p < 0.001 vs. vehicle, Mann-Whitney test. V, Vehicle; N, Nalfurafine (0.02 mg/kg, a positive control).
FIGURE 6
FIGURE 6
Central antinociceptive activities, and effects on locomotor activity and respiratory rate of HSK21542 and CR845 in mice. (A) The central antinociceptive activities were evaluated using a hot-plate test in mice at 15 min post-drug. (B) The sedative effects at 15 min post-dosing were detected using a locomotor activity test. (C, D) The effects on respiratory rate in mice were measured with whole body plethysmography. Data are presented as means ± SD (n = 10/group). (A, B) **p < 0.01, ***p < 0.001 vs. vehicle, one-way ANOVA followed by Dunnett’s test; (C, D) **p < 0.01, ***p < 0.001 vs. vehicle, two-way ANOVA followed by Dunnett’s test; ### p < 0.001 vs. vehicle, Mann-Whitney test. V, Vehicle; M, Moprhine (10 mg/kg, a positive control).
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