ArticleThe Journal of biological chemistry2012
Ligand directed signaling differences between rodent and human κ-opioid receptors.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 46 citations in OpenAlex.
- Development and Biological Characterization of Fluorescent Dynorphins for the Visualization of Kappa Opioid Receptors.Journal of medicinal chemistry · 2026Article
- Limitations and potential of κOR biased agonists for pain and itch management.Neuropharmacology · 2024Review
- Human IPSC-Derived PreBötC-Like Neurons and Development of an Opiate Overdose and Recovery Model.Advanced biology · 2024Article
- The opioid system in depression.Neuroscience and biobehavioral reviews · 2022Review
- Quantitative Systems Pharmacology and Biased Agonism at Opioid Receptors: A Potential Avenue for Improved Analgesics.International journal of molecular sciences · 2022Review
- Morphine Perinatal Exposure Induces Long-Lasting Negative Emotional States in Adult Offspring Rodents.Pharmaceutics · 2021Article
- In Silico Identification of Tripeptides as Lead Compounds for the Design of KOR Ligands.Molecules (Basel, Switzerland) · 2021Article
- Article
- In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling.International journal of molecular sciences · 2020Article
- Evaluation of Biased and Balanced Salvinorin A Analogs in Preclinical Models of Pain.Frontiers in neuroscience · 2020Article
- Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist.Frontiers in pharmacology · 2020Article
- Reactive oxygen species (ROS) generation is stimulated by κ opioid receptor activation through phosphorylated c-Jun N-terminal kinase and inhibited by p38 mitogen-activated protein kinase (MAPK) activation.The Journal of biological chemistry · 2019Article
- κ-Opioid Receptor Modulation of GABAergic Inputs onto Ventrolateral Periaqueductal Gray Dopamine Neurons.Molecular neuropsychiatry · 2019Article
- Effects of NOP-Related Ligands in Nonhuman Primates.Handbook of experimental pharmacology · 2019Article
- Estrogen Regulation of GRK2 Inactivates Kappa Opioid Receptor Signaling Mediating Analgesia, But Not Aversion.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Selective κ receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice.British journal of pharmacology · 2017Article
- Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor.Cellular signalling · 2017Article
- Human native kappa opioid receptor functions not predicted by recombinant receptors: Implications for drug design.Scientific reports · 2016Article
- The G-protein biased partial κ opioid receptor agonist 6'-GNTI blocks hippocampal paroxysmal discharges without inducing aversion.British journal of pharmacology · 2016Article
- Functional selectivity of kappa opioid receptor agonists in peripheral sensory neurons.The Journal of pharmacology and experimental therapeutics · 2015Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
KOR activation of Gβγ dependent signaling results in analgesia, whereas the dysphoric effects of KOR agonists are mediated by a different pathway involving G protein receptor kinase and non-visual arrestin. Based on this distinction, a partial KOR agonist that does not efficiently activate arrestin-dependent biased signaling may produce analgesia without dysphoria. No KOR-selective partial agonists are currently available, and preclinical assessment is complicated by sequence differences between rodent (r) and human (h) KOR. In this study, we compared the signaling initiated by the available partial agonists. Pentazocine was significantly more potent at activating p38 MAPK in hKOR than rKOR expressed in HEK293 cells but equally potent at arrestin-independent activation of ERK1/2 in hKOR and rKOR. Similarly, butorphanol increased phospho-p38-ir in hKOR-expressing cells but did not activate p38 in rKOR-HEK293. Like pentazocine, butorphanol was equally efficacious at activating ERK1/2 in rKOR and hKOR. In contrast, levorphanol, nalorphine, and U50,488 did not distinguish between hKOR and rKOR in p38 MAPK activation. Consistent with its low potency at p38 activation, pentazocine did not produce conditioned place aversion in mice. hKOR lacks the Ser-369 phosphorylation site in rKOR required for G protein receptor kinase/arrestin-dependent p38 activation, but mutation of the Ser-358 to asparagine in hKOR blocked p38 activation without affecting the acute arrestin-independent activation of ERK1/2. This study shows that hKOR activates p38 MAPK through a phosphorylation and arrestin-dependent mechanism; however, activation differs between hKOR and rKOR for some ligands. These functional selectivity differences have important implications for preclinical screening of partial KOR agonists.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.