Article
Pharmacology & Pharmacy
Nokomis Ramos-Gonzalez, Sam Groom, Katy J. Sutcliffe, Sukhvinder Bancroft, Chris P. Bailey, Richard B. Sessions, Graeme Henderson, Eamonn Kelly
Summary: The illicit use of fentanyl-like drugs and the resulting overdose deaths is a major problem. This study compared the efficacy and signaling bias of different fentanyls, and found that carfentanil is biased towards beta-arrestin.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Medicine, Research & Experimental
Siyan Liao, Kai Tan, Cecilia Floyd, Daegun Bong, Michael James Pino, Chun Wu
Summary: This study compared the binding and action mechanisms of the MOR biased agonist PZM21 and morphine to the mu-opioid receptor, revealing that PZM21 preferentially activates the G protein pathway over the beta-arrestin pathway. The interaction between PZM21 and MOR led to conformational changes and altered amino acid interactions within the receptor, potentially facilitating G protein binding.
Article
Pharmacology & Pharmacy
Liang Ye, Chunmei Li, Wanglin Jiang, Yifei Yang, Wenyan Wang, Haibo Zhu, Zhengping Hu, Ning Li, Xiaobo Cen, Hongbo Wang, Jingwei Tian
Summary: This study evaluated the subacute toxicity of LPM3480392 in rats and found that it exhibited good safety characteristics compared to other opiates. However, high doses of LPM3480392 still resulted in toxicity in certain tissues.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Neurosciences
Peng Huang, Chongguang Chen, Danni Cao, Melody Huang, Lee-Yuan Liu-Chen
Summary: This study demonstrates that agonist-promoted KOR phosphorylation plays important roles in U50,488H-induced tolerance and conditioned place aversion (CPA) in a sex-dependent manner, without affecting acute U50,488H-induced anti-pruritic and hypo-locomotor effects. These results are the first to show sex differences in the effects of GPCR phosphorylation on GPCR-mediated behaviors.
Article
Peripheral Vascular Disease
Jacob K. Meariman, Jane C. Sutphen, Juan Gao, Daniel R. Kapusta
Summary: This study found that nalfurafine enhances the diuretic effects of standard-of-care diuretics without causing excessive loss of electrolytes, offering a new approach to treat cardiovascular conditions.
Article
Pharmacology & Pharmacy
Alexander R. French, Richard M. van Rijn
Summary: Kappa opioid receptor (icOR) agonists are considered safer alternatives to clinically used mu opioid receptor (mu OR) analgesics with no abuse liability and respiratory depression effects. However, they have their own limiting adverse effects that hinder clinical translation. Recent studies suggest that these effects may be due to distinct intracellular signaling pathways, leading to the hypothesis that biased icOR agonists away from ll-arrestin signaling could have improved therapeutic windows. Overall, G-protein-biased icOR agonists generally have better therapeutic windows compared to unbiased agonists, although study design limits strong conclusions in this regard. The development of biased icOR agonists and new tools in the field puts icOR research in a position to advance our understanding and translation of biased icOR agonists to clinical use.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Pharmacology & Pharmacy
Chongguang Chen, Peng Huang, Kathryn Bland, Mengchu Li, Yan Zhang, Lee-Yuan Liu-Chen
Summary: The study found that there was no connection between agonist-promoted KOR-mediated conditioned place aversion and agonist-induced KOR phosphorylation and internalization in male mice.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Sam Groom, Nina K. Blum, Alexandra E. Conibear, Alexander Disney, Rob Hill, Stephen M. Husbands, Yangmei Li, Lawrence Toll, Andrea Kliewer, Stefan Schulz, Graeme Henderson, Eamonn Kelly, Chris P. Bailey
Summary: This study confirmed that Compound 1 is a G protein-biased mu agonist that can induce substantial rapid receptor desensitisation in mammalian neurons. However, contrary to previous assumptions, the desensitisation effect of Compound 1 is dependent on G protein-coupled receptor kinase (GRK).
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Reproductive Biology
Bin Liu, Hongyu Chen, Chunmei Li, Yana Guan, Wanglin Jiang, Hanrong Wang, Wei Guo, Wen Wen, Xiaobo Cen, Hongbo Wang, Jingwei Tian
Summary: Opioids are effective for pain management, but their misuse and abuse have become a medical concern, especially for users of child-bearing age. A new mu-opioid receptor (MOR) biased agonist, LPM3480392, has been developed as an alternative with better therapeutic ratios. Studies on rats showed that LPM3480392 had mild effects on reproductive and developmental outcomes, supporting its potential as a novel analgesic.
REPRODUCTIVE TOXICOLOGY
(2023)
Article
Chemistry, Medicinal
Robert Root-Bernstein
Summary: This paper proposes the design of combination opioid-adrenergic tethered compounds to enhance efficacy and specificity, lower dosage, increase duration of activity, decrease side effects, and reduce risk of developing tolerance and/or addiction. Recent mechanistic research suggests that dual occupancy of opioid and adrenergic receptors can improve the efficacy of drugs and inhibit the development of tolerance.
Article
Behavioral Sciences
Sally L. Huskinson, Donna M. Platt, C. Austin Zamarripa, Kristen Dunaway, Morgan Brasfield, Thomas E. Prisinzano, Bruce E. Blough, Kevin B. Freeman
Summary: KOR agonists have potential as treatments for pain, itch, and substance-use disorders, but typical KOR agonists have side effects. This study found that biased KOR agonists have fewer and milder side effects compared to typical KOR agonists. Additionally, the combination of KOR and MOR agonists resulted in different behavioral effects.
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
(2022)
Article
Neurosciences
Toshinori Yoshioka, Daisuke Yamada, Eri Segi-Nishida, Hiroshi Nagase, Akiyoshi Saitoh
Summary: This study investigates the effects of DOP agonist KNT-127 on the pathophysiological factors of depression in cVSDS mice. KNT-127 improves social interaction behaviors and corticosterone levels in cVSDS mice, as well as regulates neurogenesis and neuroinflammation. It also suppresses microglial overactivation in the hippocampal dentate gyrus.
Article
Neurosciences
Kotaro Sakamoto, Daisuke Yamada, Nanami Yamanaka, Moeno Nishida, Keita Iio, Hiroshi Nagase, Akiyoshi Saitoh
Summary: The study aimed to elucidate the mechanisms causing tremor-like behaviors induced by SNC80, a DOP agonist. Results showed that SNC80 induced tremor-like behaviors in mice by activating glutamatergic neurons, while another DOP agonist, KNT-127, did not cause tremor-like behaviors and led to lower extracellular glutamate levels in the hippocampus. Further clinical studies on KNT-127 as a DOP agonist with low risk of convulsions and potential antinociceptive and antidepressant effects are recommended.
Article
Biochemistry & Molecular Biology
Maria Dumitrascuta, Charlotte Martin, Steven Ballet, Mariana Spetea
Summary: There is an unmet clinical need for new pharmaceuticals for pain management that are effective and safe. Current pharmacotherapy using opioid drugs has serious side effects, leading to the opioid crisis. Multifunctional ligands that activate more than one receptor offer a promising approach for pain treatment with fewer adverse effects. A recent study reported on a bifunctional MOR agonist/NPFFR antagonist peptidomimetic, KGFF09, which showed antinociceptive effects in mice with reduced side effects. The study further investigated the antinociceptive properties of KGFF09 in a mouse model of visceral pain and its potential for opioid-related liabilities. KGFF09 exhibited effective inhibition of pain behavior without the usual side effects associated with MOR agonists like rewarding effects and sedation/locomotor impairment. This suggests that the development of dual MOR agonists/NPFFR antagonists could be a promising treatment for various pain conditions.
Article
Pharmacology & Pharmacy
Eliyahu Dremencov, Daniil Grinchii, Zuzana Romanova, Pavol Chomanic, Lubica Lacinova, Daniela Jezova
Summary: Chronic treatment with the non-peptide agonist SNC80 increases excitability of hippocampal glutamate and ventral tegmental area dopamine neurons, leading to anxiolytic effects. However, it does not affect the ability to cope with stress or habituation processes in a novel environment.
PHARMACOLOGICAL REPORTS
(2023)
Letter
Public, Environmental & Occupational Health
Johannes Burtscher, Gregoire P. Millet, Martin Burtscher
AMERICAN JOURNAL OF PREVENTIVE MEDICINE
(2023)
Letter
Public, Environmental & Occupational Health
Martin Burtscher, Michael Philadelphy, Johannes Burtscher, Rudolf Likar
JOURNAL OF TRAVEL MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Johannes Burtscher, Robert T. Mallet, Vincent Pialoux, Gregoire P. Millet, Martin Burtscher
Summary: In this article, the authors review the current understanding of how the human body adapts to low and high oxygen levels and discuss their potential therapeutic and performance-enhancing applications. They highlight the importance of hypoxia conditioning as a preparation for severe hypoxic insults and the potential benefits of combining it with hyperoxic interventions in the treatment of chronic diseases and for performance enhancement.
ANTIOXIDANTS & REDOX SIGNALING
(2022)
Editorial Material
Public, Environmental & Occupational Health
Johannes Burtscher, Barbara Strasser, Gregoire P. Millet, Martin Burtscher
Summary: Traveling to high-altitude destinations carries risks such as high-altitude sicknesses and impaired sleep and performance. The benefits of antioxidant supplementation are inconclusive, leading to a lack of clear clinical guidelines. This article highlights the potential of the antioxidant compound melatonin, which surprisingly has been poorly studied in high-altitude settings.
JOURNAL OF TRAVEL MEDICINE
(2022)
Article
Sport Sciences
Johannes Burtscher, Gregoire P. Millet, Hannes Gatterer, Karin Vonbank, Martin Burtscher
Summary: The decline in pulmonary function affects maximal oxygen consumption and regular physical activity can slow down this aging process and preserve pulmonary function and maximal oxygen consumption.
Editorial Material
Geriatrics & Gerontology
Johannes Burtscher, Andrea Ticinesi, Gregoire P. Millet, Martin Burtscher, Barbara Strasser
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE
(2022)
Article
Behavioral Sciences
Johannes Burtscher, Martin Niedermeier, Katharina Huefner, Erwin van den Burg, Martin Kopp, Ron Stoop, Martin Burtscher, Hannes Gatterer
Summary: Mechanisms of adaptation to hypoxia play a role in the etiopathogenesis of anxiety and depressive disorders, and controlling hypoxia responses could be a novel treatment strategy.
NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
(2022)
Review
Cell Biology
Antoine Raberin, Johannes Burtscher, Philippe Connes, Gregoire P. Millet
Summary: Hypoxia, caused by insufficient oxygen availability, is a severe threat to human health and is implicated in the development of many diseases. However, controlled hypoxia interventions have the potential to improve cardiovascular health. Blood rheology, often overlooked, plays a role in vascular health and can be influenced by aging and hypoxia exposure. This review discusses the changes in blood viscosity and its determinants related to hypoxia and aging, and focuses on the risks and benefits of hemorheological changes during hypoxia exposure in older individuals and its clinical relevance for vascular disorders.
AGEING RESEARCH REVIEWS
(2022)
Review
Cell Biology
Johannes Burtscher, Afsaneh Soltany, Nishant P. P. Visavadiya, Martin Burtscher, Gregoire P. Millet, Kayvan Khoramipour, Andy V. V. Khamoui
Summary: Mitokines are signaling molecules that enable communication of local mitochondrial stress to distant cells and tissues. They play a crucial role in mediating exercise-derived and dietary strategy-related health benefits, such as healthy aging. Maintaining balanced mitokine levels is important for inter-tissue cross talk and preventing age-related diseases. While low levels of mitokines impair inter-organ crosstalk, excessive concentrations can have deleterious consequences.
Review
Biochemistry & Molecular Biology
Robert T. Mallet, Johannes Burtscher, Vincent Pialoux, Qadar Pasha, Yasmin Ahmad, Gregoire P. Millet, Martin Burtscher
Summary: High-altitude illnesses result from acute exposure to high altitude/hypoxia. Understanding molecular mechanisms is essential for optimizing hypoxic acclimatization for efficient prophylaxis and treatment of these illnesses.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Editorial Material
Sport Sciences
Martin Burtscher, Martin Kopp, Gregoire P. Millet, Johannes Burtscher, Gerhard Ruedl
BRITISH JOURNAL OF SPORTS MEDICINE
(2023)
Review
Biochemistry & Molecular Biology
Johannes Burtscher, Erich Hohenauer, Martin Burtscher, Gregoire P. Miller, Margit Egg
Summary: Reduced oxygen availability can lead to cell and organ damage. Hypoxia inducible factors (HIFs) and mitochondria play a crucial role in the cellular response to hypoxia and help to counteract its detrimental consequences. Understanding the interaction between HIFs and mitochondria is essential for tackling hypoxia-related pathologies and harnessing the health benefits of controlled hypoxia exposures.
FREE RADICAL BIOLOGY AND MEDICINE
(2023)
Review
Neurosciences
Johannes Burtscher, Tom Citherlet, Alba Camacho-Cardenosa, Marta Camacho-Cardenosa, Antoine Raberin, Bastien Krumm, Erich Hohenauer, Margit Egg, Mona Lichtblau, Julian Mueller, Elena A. Rybnikova, Hannes Gatterer, Tadej Debevec, Sebastien Baillieul, Giorgio Manferdelli, Tom Behrendt, Lutz Schega, Hannelore Ehrenreich, Gregoire P. Millet, Max Gassmann, Christoph Schwarzer, Oleg Glazachev, Olivier Girard, Sophie Lalande, Michael Hamlin, Michele Samaja, Katharina Huefner, Martin Burtscher, Gino Panza, Robert T. Mallet
Summary: Intermittent hypoxia can have both positive and negative effects on health, depending on factors such as intensity, duration, and frequency of exposure. Adaptive responses to hypoxia can protect cells from future insults, improve resilience and function, and enhance mental and physical performance.
JOURNAL OF PHYSIOLOGY-LONDON
(2023)
Review
Sport Sciences
Antoine Raberin, Johannes Burtscher, Tom Citherlet, Giorgio Manferdelli, Bastien Krumm, Nicolas Bourdillon, Juliana Antero, Letizia Rasica, Davide Malatesta, Franck Brocherie, Martin Burtscher, Gregoire P. Millet
Summary: This comprehensive review explores the impact of sex differences on physiological responses to hypoxia, emphasizing the sensitivity of ventilatory responses and greater vascular reactivity in women. While significant sex-based differences were not observed in cardiac hemodynamic changes during hypoxia, hematological responses to hypoxia do not differ significantly between sexes, but are sensitive to fluctuations in sex hormones. Further investigation is needed to understand the influence of the menstrual cycle and menopause on physiological responses to hypoxia.
Article
Neurosciences
Melek Firat Altay, Senthil T. Kumar, Johannes Burtscher, Somanath Jagannath, Catherine Strand, Yasuo Miki, Laura Parkkinen, Janice L. Holton, Hilal A. Lashuel
Summary: The abnormal aggregation and accumulation of alpha-synuclein (aSyn) in the brain is a defining hallmark of synucleinopathies. Various forms of aSyn pathology were identified using an expanded antibody panel, and it was found that aSyn can undergo phosphorylation during disease processes.
NPJ PARKINSONS DISEASE
(2023)