Peripheral Kappa Opioid Receptor Signaling Takes on a Central Role

Naser, Paul Vincent; Kuner, Rohini

doi:10.1016/j.neuron.2018.09.006

Cited by 9 publications

(7 citation statements)

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“…This is because the two κ -receptor agonists inhibit the sensitization of peripheral pain κ -opioid receptors and the excitatory neurotransmission between the afferent nerves expressing κ -opioid receptors and the superficial neurons of the spinal cord that process pain signals. These functional κ -opioid receptors have abundant innervation not only for skin but also for visceral organs, which indicates that κ -opioid receptors are of great significance in inhibiting visceral pain [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Analgesic Effects of Different κ-Receptor Agonists Used in Daytime Laparoscopic Cholecystectomy

Zhou

Wang

et al. 2021

BioMed Research International

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Background. Comparing the effect of two different κ-receptor agonists, nalbuphine and oxycodone, and regular morphine in patients for prophylactic analgesia of acute pain after daytime laparoscopic cholecystectomy. Methods. One hundred and twenty-four patients undergoing laparoscopic cholecystectomy were randomly allocated to receive nalbuphine (group N), oxycodone (group O), and morphine (group M). The three groups were all given intravenous injection (iv.) of 0.15 mg/kg injection before incision and 0.05 mg/kg injection at the end of pneumoperitoneum. The Visual Analogue Scale (VAS) scores (incision, visceral, and shoulder) and Ramsay sedation scores at 1, 2, 4, 8, 12, 16, 20, and 24 hours after surgery, the time of extubation, the incidence of postoperative adverse events, the satisfaction of pain treatment, and the duration of stay after surgery were all recorded. Results. Compared with group M, the VAS scores of visceral pain at rest decreased in group N and group O at 1-8 h after surgery ( P < 0.05 ). The VAS scores of visceral pain at movement in group N decreased longer than those in group O ( P < 0.05 ). Compared with that of group M, the postoperative time in Ramsay sedation score of group O increased longer than that of group N ( P < 0.05 ). Compared with group N, patients had worse sleep quality in group O, longer length of stay in group M, and lower satisfaction in both groups. Conclusion. Compared with morphine, prophylactic use of the κ-receptor agonists, nalbuphine and oxycodone, during laparoscopic cholecystectomy can reduce postoperative visceral pain. Furthermore, the nalbuphine group had fewer adverse reactions, better analgesia, and better satisfaction.

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Section: Discussionmentioning

confidence: 99%

Analgesic Effects of Different κ-Receptor Agonists Used in Daytime Laparoscopic Cholecystectomy

Zhou

Wang

et al. 2021

BioMed Research International

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“…Functionally, these reduce nociception and neurogenic (afferentfibre) plasma extravasation (Snyder et al, 2018). KOP receptor activation on primary afferents in the dorsal root ganglion seems to lack the most problematic peripherally mediated MOP receptor side-effects, such as gastrointestinal stasis (Riviere, 2004), nausea and itch (Riviere, 2004;Naser and Kuner, 2018), even suppressing MOP receptor-mediated tolerance (Vanderah et al, 2000;Wang et al, 2009). Hence, it is not surprising that KOP receptor is a validated target for itch and visceral and inflammatory pain.…”

Section: Introductionmentioning

confidence: 99%

Design and development of novel, short, stable dynorphin-based opioid agonists for safer analgesic therapy

Lohman

Tupally²,

Kandale³

et al. 2023

Front. Pharmacol.

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Kappa opioid receptors have exceptional potential as an analgesic target, seemingly devoid of many problematic Mu receptor side-effects. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally mediated side-effects limit clinical translation. We modify endogenous dynorphin peptides to improve drug-likeness and develop safer KOP receptor agonists for clinical use. Using rational, iterative design, we developed a series of potent, selective, and metabolically stable peptides from dynorphin 1–7. Peptides were assessed for in vitro cAMP-modulation against three opioid receptors, metabolic stability, KOP receptor selectivity, desensitisation and pERK-signalling capability. Lead peptides were evaluated for in vivo efficacy in a rat model of inflammatory nociception. A library of peptides was synthesised and assessed for pharmacological and metabolic stability. Promising peptide candidates showed low nanomolar KOP receptor selectivity in cAMP assay, and improved plasma and trypsin stability. Selected peptides showed bias towards cAMP signalling over pERK activity, also demonstrating reduced desensitisation. In vivo, two peptides showed significant opioid-like antinociception comparable to morphine and U50844H. These highly potent and metabolically stable peptides are promising opioid analgesic leads for clinical translation. Since they are somewhat biased peptide Kappa agonists they may lack many significant side-effects, such as tolerance, addiction, sedation, and euphoria/dysphoria, common to opioid analgesics.

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“…The actions of peripherally-restricted KOR agonists are restricted to peripheral sites due to their low penetration into the brain, and the CNS-associated side effects associated with this can be significantly ameliorated or even completely abolished. The peripherally-restricted KOR agonists had analgesic, anti-inflammatory and antipruritic effects ( Naser and Kuner, 2018 ). Till now, some peripherally-restricted KOR agonists, including ICI-204448, GR-94839, asimadoline, ADL-10-0116, FE200665 (CR665) and difelikefalin (CR845), have been successfully identified ( Barber et al, 1994 ; Binder et al, 2001 ; Vanderah et al, 2004 ; Negus et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Gou

et al. 2021

Front. Pharmacol.

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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.

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Peripheral Kappa Opioid Receptor Signaling Takes on a Central Role

Cited by 9 publications

References 10 publications

Analgesic Effects of Different κ-Receptor Agonists Used in Daytime Laparoscopic Cholecystectomy

Analgesic Effects of Different κ-Receptor Agonists Used in Daytime Laparoscopic Cholecystectomy

Design and development of novel, short, stable dynorphin-based opioid agonists for safer analgesic therapy

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

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