Pharmacology Biochemistry and Behavior
Volume 254, September 2025, 174056
by Lee-Yuan Liu-Chen, Peng Huang
Highlights
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KOR agonists produce additive analgesic effect with MOR agonists.
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KOR agonists reduce reinforcing properties and side effects of MOR agonists.
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KOR agonists when used with MOR agonists for analgesia may prevent opioid use disorder.
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KOR agonists decrease reinforcing properties of cocaine.
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KOR agonists may be useful for treatment of cocaine use disorder.
Abstract
Reports in the 1990s and 2000s showed that kappa opioid receptor (KOR) agonists might be promising for treatment and/or prevention of opioid use disorder (OUD) and cocaine use disorder (CUD). However, the side effects associated with KOR agonists available at the time, such as psychotomimesis, dysphoria and sedation, prevented clinical development. Subsequently, nalfurafine and recently triazole 1.1 and oxa-noribogaine, three centrally acting KOR agonists devoid of such side effects, have been studied in animal models of OUD and CUD. By and large, earlier findings with typical KOR agonists were replicated with nalfurafine and in limited studies with triazole 1.1 and oxa-noribogaine. KOR agonists reduced reinforcing effects of mu opioid receptor (MOR) agonists and decreased tolerance to and dependence on MOR agonists. Oxa-noribogaine suppressed cue-induced reinstatement of morphine and fentanyl seeking. KOR agonists countered itch elicited by MOR agonists and produced additive analgesic effects with MOR agonists, thus allowing use of lower doses of MOR and KOR agonists, resulting in lower degrees of MOR-related side effects (such as respiratory depression) and typical KOR-associated side effects. In addition, KOR agonists attenuated locomotor sensitization and conditioned place preference sensitization following repeated cocaine, reduced acquisition and maintenance of cocaine self-administration and decreased cocaine-induced increase in extracellular dopamine. KOR agonists also suppressed cocaine priming-induced reinstatement of cocaine seeking. Therefore, a combination of a KOR agonist and a MOR agonist or a compound with dual KOR/MOR agonist activities when used as analgesics will deter escalation use of MOR agonists, thus prevent OUD, and KOR agonists may be useful for treatment of cocaine abuse and relapse. Importantly, KOR agonists with no or fewer side effects of typical KOR agonists should be further investigated in animal models of OUD and CUD, particularly those that simulate stress-, cue- and drug priming-induced relapse for potential clinical development.
Introduction
In the US more than one million people have died since 1999 from overdose of drugs of abuse (https://www.countyhealthrankings.org/health-data/health-factors/health-behaviors/alcohol-and-drug-use/drug-overdose-deaths). The number of reported opioid overdose deaths increased dramatically in recent years, with 81,083 deaths in 2023 (the most recent CDC data) (https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2024/20240515.htm). In the same year, 29,918 people died from overdoses involving cocaine (https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2024/20240515.htm). Many more are suffering from opioid use disorder (OUD)1 or/and cocaine use disorder (CUD). While overdose deaths involving opioids decreased in 2023 compared with 2022, overdose deaths involving cocaine and psychostimulants (like methamphetamine) increased. Unlike OUD, there are no effective medications for CUD. The % of overdose deaths in US involving both fentanyl and stimulants increased from 0.6 % (235) in 2010 to 32.3 % (34,429) in 2021 (Friedman and Shover, 2023). OUD and CUD are often co-morbid. Substance use disorder is a medical, societal, economic, and public health issue, that exacts terrible tolls on the individuals and the society. Therefore, developing drugs effective for treatment of substance use disorder (SUD) is critically important. SUD encompasses compulsive use of many drugs of abuse despite of negative consequences. This review will focus on OUD and CUD.
The kappa opioid receptor (KOR) is one of the three opioid receptors. Studies published as early as 1990s showed that KOR agonists reduced reinforcing properties of opioids and cocaine. KOR agonists prevented morphine-induced conditioned place preference (CPP) at low doses that do not cause conditioned place aversion (CPA) (Bolanos et al., 1996; Funada et al., 1993) and reduced self-administration (SA) of morphine, oxycodone, or heroin in rats and mice at doses that do not affect water SA (Glick et al., 1995; Kuzmin et al., 1997; Xi et al., 1998). KOR agonists also reduced acquisition and maintenance of cocaine SA (Glick et al., 1995; Mello and Negus, 1998, Mello and Negus, 2000; Negus et al., 1997) and attenuated cocaine-induced reinstatement of extinguished cocaine-seeking behavior in rats and monkeys (Morani et al., 2009; Schenk et al., 1999). However, development of KOR agonists for clinical use has been limited by side effects, most importantly dysphoria, psychotomimesis, and sedation (Pande et al., 1996; Pfeiffer et al., 1986; Walsh et al., 2001), except for nalfurafine (formerly named TRK-820)[reviewed in(Miyamoto et al., 2022; Zhou et al., 2022)] and, the peripherally acting difelikefalin (Fishbane et al., 2020; Lipman and Yosipovitch, 2021). Nalfurafine has been used in Japan since 2017 and difelikefalin was approved in the USA in 2021, both for pruritus associated with kidney dialysis. In addition, in preclinical studies triazole 1.1 showed promises as a selective KOR agonist without adverse effects associated with typical KOR agonists (Brust et al., 2016; Zhou et al., 2013).
Herein pharmacology of nalfurafine and triazole 1.1 is briefly described. Then evidence is reviewed for effects of KOR agonists on reinforcing effects of opioids and cocaine and reinstatement of drug seeking after extinction of SA behaviors. With the availability of KOR agonists that show no or fewer unwanted side effects, the notion that KOR agonists may be useful for the prevention and treatment of SUD warrants re-evaluation.
Section snippets
Nalfurafine
Nalfurafine is a highly potent and moderately selective KOR agonist (Cao et al., 2020; Nagase et al., 1998; Wang et al., 2005). Using [35S]GTPγS binding, we have shown that nalfurafine is a potent KOR full agonist (EC50 = 0.097 nM) and MOR partial agonist with 32× KOR/MOR and 242× KOR/DOR selectivity, respectively (Cao et al., 2020). By inhibition of [3H]diprenorphine binding, we determined its Ki to be 0.075 nM for the KOR with 69× KOR/MOR selectivity and 214× KOR/DOR selectivity(Wang et al.,
U50,488H and the dynorphin A analog E-2078
Funada et al. (1993) reported that in male ddY mice, an outbred strain, morphine (3 or 5 mg/kg, s.c.) produced significant CPP, whereas U50,488H (1 mg/kg, s.c.) and the dynorphin A analog E-2078 (0.1 mg/kg, s.c.) induced a slight, nonsignificant CPA. Morphine (3 mg/kg)-induced CPP was abolished by pretreatment with U50,488H (1 mg/kg) and significantly decreased by pretreatment with E-2078 (0.1 mg/kg). The inhibitory effects of U50,488H and E-2078 were antagonized by the KOR antagonist
U50,488
Pretreatment of C57BL/6 mice with nalfurafine (3 μg/kg and 10 μg/kg, s.c.) or U50,488 (3 mg/kg, s.c.) for 15 min before cocaine conditioning blocked cocaine (15 mg/kg)-induced CPP, while these drugs alone did not cause CPA or sedation in the rotarod assay (Dunn et al., 2020). Pretreatment of mice with 10 μg/kg nalfurafine or 3 mg/kg U50,488 immediately before testing potentiated cocaine SA (0.5 mg/kg/infusion). Further, 10 μg/kg nalfurafine also increased progressive ratio break point,
KOR agonists vs. KOR antagonists for the prevention and treatment of SUDs
Koob proposed a conceptual framework of SUDs, which is a three-stage cycle – binge/intoxication, withdrawal/negative affect, and preoccupation / anticipation (Koob, 2020, Koob, 2021, Koob, 2022). The three stages represent dysregulation in three functional domains: incentive salience and/or habits, negative emotional states, and executive function, respectively. Repeated use of drugs of abuse leads to escalating drug use and development tolerance and/or dependence (binge/intoxication) and
Centrally acting novel KOR agonists with fewer side effects
Centrally acting KOR agonists that produce fewer side effects typically associated with KOR agonists, such as nalfurafine, RB64, triazole 1.1, oxa-noribogaine, LOR17 and HS666, makes it feasible to use these compounds for prevention and treatment of SUD. Among these compounds, only nalfurafine is used clinically. As mentioned above, nalfurafine has been approved and used in Japan and South Korea for management of systemic itch associated with kidney dialysis or chronic liver diseases without
Conclusions
There was a large body of literature in 1990s and 2000s showing that KOR agonists reduced reinforcing properties of opioids and cocaine and suppressed reinstatement of opioids or cocaine seeking. However, because of the side effects associated with KOR agonists available at the time, the investigations were limited to preclinical studies in animal models. Subsequently, centrally acting KOR agonists that showed no or lower degrees of side effects have become available, including nalfurafine,
CRediT authorship contribution statement
Lee-Yuan Liu-Chen: Writing – review & editing, Writing – original draft, Project administration, Investigation, Funding acquisition, Conceptualization. Peng Huang: Writing – review & editing, Conceptualization.
Source: https://www.sciencedirect.com/science/article/abs/pii/S0091305725001030