Targeting peripheral κ-opioid receptors for the non-addictive treatment of pain

Abstract

Drug addiction to prescription mu-opioid agonists used in the setting of pain is a major public health threat, affecting millions of Americans. Kappa opioid agonists (KOAs) may serve as a possible solution. KOAs have demonstrated indistinguishable analgesic activity relative to mu-opioid agonists in models of acute and chronic pain; however, conventional KOAs suffer from central nervous system-mediated psychoactive side-effects. In this review, we discuss our efforts, as well as other’s efforts, in developing peripherally-restricted kappa opioid agonists with retained or improved efficacy in rodent models of pain. Results indicate that our lead compound JT09 acts as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired central nervous system-mediated side-effects. In this review, we discuss our former results and future directions.

Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration

“…Overall, these results substantiate the efficacy of compounds 2 and 7 as potent, systemically active KOR-selective agonists, which suggests that these peptides might be promising candidates for further pharmacological characterization. − The novel compounds are efficacious as antinociceptive agents following peripheral administration on KOR. Among them, peptide 7 shows a favorable pharmacokinetic profile since it is not detectable in mouse brain.…”

The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

“…KORs are currently being investigated as a therapeutic target for the treatment of pain because KOR activation has potent anti-nociceptive effects in various models of acute (mechanical, thermal and chemical) ( Briggs et al, 1998 ; Beck et al, 2019 ; Escudero Lara et al, 2021 ), inflammatory ( Paton et al, 2017 ), neuropathic ( Sounvoravong et al, 2004 ), and cancer pain ( Edwards et al, 2018 ). The use of KOR agonists for the treatment of pain are therapeutically desirable due to the presence of anti-nociceptive effects without abuse potential ( Beck and Dix, 2019 ) or respiratory depressive effects ( Viscusi et al, 2021 ; Wang et al, 2021 ).…”

“…CR845 (also known as difelikefalin) and CR665 (also known as FE-200665) both exhibit potent anti-nociceptive effects in preclinical models of inflammatory, visceral ( Binder et al, 2001 ; Arendt-Nielsen et al, 2009 ) and neuropathic pain without gastrointestinal side effects ( Gardell et al, 2008 ). CR845 completed phase III clinical trials ( Beck and Dix, 2019 ) and recently received FDA approval in the United States under the name Korsuva for the treatment of pruritis in adults with chronic kidney disease who are undergoing haemodialysis ( Deeks, 2021 ). In a single-dose crossover study involving healthy volunteers, intravenous (i.v.)…”

“…For a recent review on the role of DOR in modulating nociception see Quirion et al (2020) . Agonists targeting the KOR have also received growing interest ( Kivell and Prisinzano, 2010 ; Bohn and Aubé, 2017 ; Beck and Dix, 2019 ; Mores et al, 2019 ; Paton et al, 2020a ; Mercadante and Romualdi, 2020 ).…”

TRPA1 analgesia is mediated by kappa opioid receptors

“…The percentage of KOR expressing mouse DRG neurons is only about 10-11%, similar to the percentage seen in rats (Ji et al, 1995, Schafer et al, 1994, Zhang et al, 1998); however, altered activity in these neurons can have a marked analgesic effect. For example, the KOR-specific agonist U50,488 has a local analgesic action when injected into the paw (Auh and Ro, 2012, Moon et al, 2016) and peripherally restricted KOR agonists are analgesic (Beck and Dix, 2019, Kivell and Prisinzano, 2010, Vanderah, 2010).…”