The Kappa Opioid Receptor Is Associated With Naltrexone-Induced Reduction of Drinking and Craving

Laat, Bart de; Goldberg, Alissa; Shi, Julia; Tetrault, Jeanette M.; Nabulsi, Nabeel; Zheng, Ming-Qiang; Najafzadeh, Soheila; Gao, Hong; Kapinos, Michael; Ropchan, Jim; O’Malley, Stephanie S.; Huang, Yiyun; Morris, Evan D.; Krishnan‐Sarin, Suchitra

doi:10.1016/j.biopsych.2019.05.021

Cited by 29 publications

(21 citation statements)

References 66 publications

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“…A compound structurally related to LY2456302, 11 C-LY2795050, has also been used as κ-receptor PET radiotracer in humans (de Laat et al, 2019; Naganawa et al, 2015a). LY2795050 (3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide) has relative binding selectivity in vitro for κ−receptors over µ- and δ-receptors ( K i values of 0.72, 25.8 and 153nM, respectively) (Zheng et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Profile of a short-acting κ-antagonist, LY2795050, on self-grooming behaviors, forced swim test and locomotor activity: sex comparison in mice

et al. 2021

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Background: Novel short-acting κ(kappa)-opioid receptor selective antagonists are translational tools to examine the impact of the κ-receptor/dynorphin system in assays related to central nervous system dysfunction (e.g., substance use disorders, anhedonia and depression). The effects of such compounds have been compared in males and females under very limited conditions. Aims: The goal of this study was to examine potential sex differences in the effects of a κ-agonist and a short-acting κ-antagonist in an ethologically relevant test of anhedonia, the “splash test” of self-grooming, and also in the forced swim test and in locomotor activity. Methods: We examined the dose-dependence of grooming deficits caused by the κ-agonist U50,488 (0.1–3.2 mg/kg intraperitoneal (i.p.)) in gonadally intact adult male and female C57BL/6J mice. We then compared the effects of the short-acting κ-antagonist LY2795050 ((3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide)); 0.032–0.1 mg/kg i.p.) in blocking grooming deficits caused by U50,488 (3.2 mg/kg). The effects of LY2795050 were also studied in the forced swim test (FST). The effects of LY2795050 in blocking the locomotor depressant effects of U50,488 (10 mg/kg) were also studied. Results: U50,488 produced dose-dependent grooming deficits in male and female mice, and LY2795050 prevented these effects. In contrast, LY2795050 decreased immobility in the FST in males at a dose of 0.1 mg/kg, but not in females, up to a dose of 0.32 mg/kg. Also, LY2795050 (0.32 mg/kg) prevented and also reversed the locomotor-depressant effects of U50,488 (10 mg/kg), in males and females. Conclusions: This study further implicates the κ-receptor system in ethologically relevant aspects of anhedonia, and confirms sexual dimorphism in some behavioral effects of novel κ-antagonists.

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Section: Introductionmentioning

confidence: 99%

Profile of a short-acting κ-antagonist, LY2795050, on self-grooming behaviors, forced swim test and locomotor activity: sex comparison in mice

et al. 2021

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“…The μ‐antagonist effects of naltrexone and nalmefene have received much attention in human research (Comer et al, ; Gal & DiFazio, ; Webster et al, ). The potential importance of κ‐receptor mediated effects of these compounds in the treatment of AUD is the focus of more recent studies (de Laat et al, ). Overall, these data provide further insight into the neuroendocrine biomarker profile of these two pharmacotherapies.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, these cortisol levels were negatively correlated with alcohol craving (O'Malley et al, ). A very recent positron emission tomography neuroimaging study also showed that naltrexone‐induced reduction in alcohol intake in heavy drinkers was negatively correlated with baseline κ‐receptor availability in the striatum (de Laat et al, ).…”

Section: Introductionmentioning

confidence: 96%

Neuroendocrine effects of naltrexone versus nalmefene in humans

Butelman

Fry

Kimani

et al. 2020

Human Psychopharmacology

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Objective Naltrexone and nalmefene are approved for the treatment of alcohol use disorders, in different countries. Naltrexone is also approved for the treatment for opioid use disorders, most recently in a depot formulation. These compounds target primarily μ(mu)‐ and κ(kappa)‐opioid receptor systems, which are involved in the downstream neurobiological effects of alcohol and in the modulation of neuroendocrine stress systems. The study objective was to compare the neuroendocrine effects of naltrexone and nalmefene on adrenocorticotropic hormone (ACTH), cortisol, and prolactin, in normal volunteers. Method Adult normal volunteers (n = 11 male and n = 9 female) were studied in a stress‐minimized inpatient setting on three consecutive days, after intravenous saline, naltrexone HCl (10 mg), or nalmefene HCl (10 mg), in fixed order. ACTH, cortisol, and prolactin were analyzed pre‐injection and up to 180 min post‐injection. Results Naltrexone and nalmefene caused elevations in ACTH and cortisol compared with saline. Nalmefene had a greater effect on ACTH and cortisol, compared with naltrexone. Both compounds also caused elevations in prolactin in males (females were not examined, due to the influence of menstrual cycle on prolactin). Conclusions This study suggests that both nalmefene and naltrexone have effects potentially due to κ‐partial agonism in humans, as well as antagonist effects at μ‐receptors.

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“…In contrast, their study utilizing the KOR selective antagonist [11C]LY2795050 to compare KOR availability between nontreatment-seeking alcohol-dependent individuals (all heavy users) and healthy individuals found that KOR availability was lower in the alcohol-dependent group by both ROI and voxel-based analyses (Figure 3) (10). They also found that reductions in drinking and craving in the alcohol-dependent group after 1 week of open-label naltrexone (100 mg daily) were negatively associated with baseline KOR binding (lower KOR availability associated with greater reductions) in several regions (ROI analysis: striatum; voxelwise analysis: bilateral insula, bilateral cingulate cortex, and left prefrontal cortex), supporting a role for KOR in naltrexone's therapeutic effects (11).…”

mentioning

confidence: 81%

“…In a study using the KOR selective antagonist [ 11 C] LY2795050, baseline KOR availability was lower in multiple regions in nontreatment-seeking alcohol-dependent individuals (all heavy users) compared with healthy individuals (10). However, reductions in drinking and craving in the alcohol-dependent group after 1 week of open-label naltrexone (100 mg daily) were negatively associated with baseline KOR binding (lower KOR availability associated with greater reductions) in several regions, supporting a role for the KOR system in naltrexone's therapeutic effects (11). Reproduced under the terms of the Creative Commons Attribution License.…”

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confidence: 86%

Positron Emission Tomography: Updates on Imaging of Addiction

Sai¹,

Hurley²,

Dodda³

et al. 2019

JNP

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FIGURE 1. A wide array of positron emission tomography (PET) ligands have been developed that provide information relevant to multiple aspects of addiction (1-3). Locations of targets are approximated on this diagram, which is color-coded by functional roles. On the presynaptic side (pink), targets include neurotransmitter precursors (orange, example [ 18 F]-fluorodopa, FDOPA), modulatory receptors (yellow, examples [ 11 C] GR103545, [ 11 C] LY27950509 and [ 18 F] LY2459989 for kappa opioid receptors, KOR; [ 18 F]FMPEP for cannabinoid 1 receptors, CB1), and neurotransmitter reuptake transporters (light green, examples [ 11 C] PE2I and [ 18 F] FE-PE2I for the dopamine transporter, DAT). On the postsynaptic side (purple), targets include neurotransmitter receptors (blue, examples [ 11 C] raclopride and [ 11 C]-(1)-PHNO for dopamine D 2 and D 3 receptors, D 2 R; [ 11 C] carfentanil for mu opioid receptors, MOR; [ 18 F] LY2459989 for both mu and kappa opioid receptors; 2-[ 18 F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine for nicotinic acetylcholine receptors, nAChR). Some PET ligands target more generic functions.[ 18 F]-fluoro-deoxy-glucose (FDG) PET provides a measure of cerebral metabolic rate.

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The Kappa Opioid Receptor Is Associated With Naltrexone-Induced Reduction of Drinking and Craving

Cited by 29 publications

References 66 publications

Profile of a short-acting κ-antagonist, LY2795050, on self-grooming behaviors, forced swim test and locomotor activity: sex comparison in mice

Profile of a short-acting κ-antagonist, LY2795050, on self-grooming behaviors, forced swim test and locomotor activity: sex comparison in mice

Neuroendocrine effects of naltrexone versus nalmefene in humans

Positron Emission Tomography: Updates on Imaging of Addiction

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