{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:28Z","timestamp":1787028448300,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,17]],"date-time":"2021-04-17T00:00:00Z","timestamp":1618617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2019\/35\/D\/NZ5\/02820"],"award-info":[{"award-number":["2019\/35\/D\/NZ5\/02820"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2014\/15\/B\/NZ5\/03566"],"award-info":[{"award-number":["2014\/15\/B\/NZ5\/03566"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The opioid system is well-known for its role in modulating nociception and addiction development. However, there are premises that the endogenous opioid system may also affect blood pressure. The main goal of the present study was to determine the impact of different endogenous opioid system activity and its pharmacological blockade on blood pressure. Moreover, we examined the vascular function in hyper- and hypoactive states of the opioid system and its pharmacological modification. In our study, we used two mouse lines which are divergently bred for high (HA) and low (LA) swim stress-induced analgesia. The obtained results indicated that individuals with low endogenous opioid system activity have higher basal blood pressure compared to those with a hyperactive opioid system. Additionally, naloxone administration only resulted in the elevation of blood pressure in HA mice. We also showed that the hypoactive opioid system contributes to impaired vascular relaxation independent of endothelium, which corresponded with decreased guanylyl cyclase levels in the aorta. Together, these data suggest that higher basal blood pressure in LA mice is a result of disturbed mechanisms in vascular relaxation in smooth muscle cells. We believe that a novel mechanism which involves endogenous opioid system activity in the regulation of blood pressure will be a promising target for further studies in hypertension development.<\/jats:p>","DOI":"10.3390\/ijms22084179","type":"journal-article","created":{"date-parts":[[2021,4,18]],"date-time":"2021-04-18T22:15:13Z","timestamp":1618784113000},"page":"4179","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hypertensive Effect of Downregulation of the Opioid System in Mouse Model of Different Activity of the Endogenous Opioid System"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5910-2955","authenticated-orcid":false,"given":"Dominik S.","family":"Skiba","sequence":"first","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Post\u0119pu 36A, Jastrz\u0119biec, 05-552 Magdalenka, Poland"},{"name":"British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, University Place 126, Glasgow G12 8TA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Szczepaniak","sequence":"additional","affiliation":[{"name":"Department of Internal and Agricultural Medicine, Translational Medicine Laboratory, Collegium Medicum Jagiellonian University, Skarbowa 1, 31-121 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateusz","family":"Siedli\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Internal and Agricultural Medicine, Translational Medicine Laboratory, Collegium Medicum Jagiellonian University, Skarbowa 1, 31-121 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1321-2235","authenticated-orcid":false,"given":"Piotr","family":"Pozna\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Post\u0119pu 36A, Jastrz\u0119biec, 05-552 Magdalenka, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzena","family":"\u0141azarczyk","sequence":"additional","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Post\u0119pu 36A, Jastrz\u0119biec, 05-552 Magdalenka, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinga","family":"Jasku\u0142a","sequence":"additional","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Post\u0119pu 36A, Jastrz\u0119biec, 05-552 Magdalenka, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Religa","sequence":"additional","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Post\u0119pu 36A, Jastrz\u0119biec, 05-552 Magdalenka, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariusz","family":"Sacharczuk","sequence":"additional","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Post\u0119pu 36A, Jastrz\u0119biec, 05-552 Magdalenka, Poland"},{"name":"Faculty of Pharmacy with the Laboratory Medicine Division, Department of Pharmacodynamics, Medical University of Warsaw, Centre for Preclinical Research and Technology, Banacha 1B, 02-091 Warsaw, Poland"},{"name":"Department of Internal Medicine, Hypertension and Vascular Diseases, Medical University of Warsaw, Banacha 1A, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zbigniew","family":"Gaciong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hypertension and Vascular Diseases, Medical University of Warsaw, Banacha 1A, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1016\/S0196-0644(86)80124-X","article-title":"The Role of Endogenous Peptides in the Action of Opioid Analgesics","volume":"15","author":"Adams","year":"1986","journal-title":"Ann. Emerg. Med."},{"key":"ref_2","first-page":"57","article-title":"A Note on the Pharmacological Action of Opium Alkaloids","volume":"6","author":"Jackson","year":"1914","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_3","first-page":"I125","article-title":"The Opioid System in Cardiac and Vascular Regulation of Normal and Hypertensive States","volume":"75","author":"Feuerstein","year":"1987","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0163-7258(00)00106-6","article-title":"Opioids and Cardioprotection","volume":"89","author":"Schultz","year":"2001","journal-title":"Pharmacol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"436","DOI":"10.3389\/fphys.2016.00436","article-title":"The Impact of Opium Consumption on Blood Glucose, Serum Lipids and Blood Pressure, and Related Mechanisms","volume":"7","author":"Najafipour","year":"2016","journal-title":"Front. Physiol."},{"key":"ref_6","first-page":"182","article-title":"The Relationship of Opium Addiction with Coronary Artery Disease","volume":"1","author":"Masoomi","year":"2010","journal-title":"Int. J. Prev. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.pain.2007.05.003","article-title":"Effects of Opioid Blockade on the Modulation of Pain and Mood by Sweet Taste and Blood Pressure in Young Adults","volume":"135","author":"Lewkowski","year":"2008","journal-title":"Pain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1097\/01.psy.0000195742.24850.79","article-title":"Opioid Analgesia in Persons at Risk for Hypertension","volume":"68","author":"McCubbin","year":"2006","journal-title":"Psychosom. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/0196-9781(83)90119-5","article-title":"Dynorphins and Leu-Enkephalin in Brain Nuclei and Pituitary of WKY and SHR Rats","volume":"4","author":"Feuerstein","year":"1983","journal-title":"Peptides"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1159\/000138926","article-title":"Age-Related Changes in Opioid Peptide Concentrations in Brain and Pituitary of Spontaneously Hypertensive Rats","volume":"44","author":"Li","year":"1992","journal-title":"Pharmacology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1476-5381.1979.tb08661.x","article-title":"Naloxone Reverses the Antihypertensive Effect of Clonidine","volume":"67","author":"FARSANG","year":"1979","journal-title":"Br. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1046\/j.1474-8673.2002.00249.x","article-title":"The Effect of Nitric Oxide Synthase Blockade on Responses to Morphine in Rat Aortic Rings","volume":"22","author":"Sahin","year":"2002","journal-title":"Auton. Autacoid Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1097\/00000542-200703000-00018","article-title":"High-dose morphine impairs vascular endothelial function by increased production of superoxide anions","volume":"106","author":"Lam","year":"2007","journal-title":"J. Am. Soc. Anesthesiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"B\u0105dzy\u0144ska, B., Lipkowski, A.W., and Sadowski, J. (2016). An Antihypertensive Opioid: Biphalin, a Synthetic Non-Addictive Enkephalin Analog Decreases Blood Pressure in Spontaneously Hypertensive Rats. Pharmacol. Rep., 68.","DOI":"10.1016\/j.pharep.2015.06.006"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"B\u0105dzy\u0144ska, B., Lipkowski, A.W., Olszy\u0144ski, K.H., and Sadowski, J. (2016). Different Blood Pressure Responses to Opioids in 3 Rat Hypertension Models: Role of the Baseline Status of Sympathetic and Renin\u2013Angiotensin Systems. Can. J. Physiol. Pharmacol., 94.","DOI":"10.1139\/cjpp-2016-0111"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pozna\u0144ski, P., Lesniak, A., Bujalska-Zadrozny, M., Strzemecka, J., and Sacharczuk, M. (2019). Bidirectional Selection for High and Low Stress-Induced Analgesia Affects G-Protein Activity. Neuropharmacology, 144.","DOI":"10.1016\/j.neuropharm.2018.10.014"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0006-8993(86)91380-6","article-title":"Differentiation of Neurochemical Basis of Stress-Induced Analgesia in Mice by Selective Breeding","volume":"397","author":"Panocka","year":"1986","journal-title":"Brain Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S0006-8993(98)01141-X","article-title":"Mu and Delta Opioid Receptor Analgesia, Binding Density, and MRNA Levels in Mice Selectively Bred for High and Low Analgesia","volume":"816","author":"Kest","year":"1999","journal-title":"Brain Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"227","DOI":"10.20452\/pamw.2776","article-title":"Resistant: Hypertension, Patient, or Physician?","volume":"125","author":"Gaciong","year":"2015","journal-title":"Pol. Arch. Med. Wewn."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1097\/01.NURSE.0000554247.12754.28","article-title":"Long-Term Effects of Opioids on the Cardiovascular System","volume":"49","author":"Corbett","year":"2019","journal-title":"Nursing"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1111\/pme.12915","article-title":"Cardiac Effects of Opioid Therapy","volume":"16","author":"Chen","year":"2015","journal-title":"Pain Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1159\/000492616","article-title":"Opioids and Cardiac Arrhythmia: A Literature Review","volume":"27","author":"Behzadi","year":"2018","journal-title":"Med. Princ. Pract."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.neuropharm.2017.03.016","article-title":"Delta-opioid receptor antagonism leads to excessive ethanol consumption in mice with enhanced activity of the endogenous opioid system","volume":"118","author":"Poznanski","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1161\/01.CIR.0000158690.78503.5F","article-title":"Natural History of Hypertension Subtypes","volume":"111","author":"Verdecchia","year":"2005","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1159\/000326084","article-title":"Activation of Peripheral Opioid \u039c-Receptors in Blood Vessel May Lower Blood Pressure in Spontaneously Hypertensive Rats","volume":"87","author":"Chen","year":"2011","journal-title":"Pharmacology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1161\/01.HYP.7.5.808","article-title":"Endogenous Opiate Peptides, Stress Reactivity, and Risk for Hypertension","volume":"7","author":"McCubbin","year":"1985","journal-title":"Hypertension"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/jhh.2012.18","article-title":"Depression and Anxiety Are Associated with a Diagnosis of Hypertension 5 Years Later in a Cohort of Late Middle-Aged Men and Women","volume":"27","author":"Ginty","year":"2013","journal-title":"J. Hum. Hypertens."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"259","DOI":"10.21037\/atm.2017.03.99","article-title":"Hypertension and Cognitive Impairment","volume":"5","author":"Aronow","year":"2017","journal-title":"Ann. Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.bbr.2017.03.015","article-title":"Naloxone Exacerbates Memory Impairments and Depressive-like Behavior after Mild Traumatic Brain Injury (MTBI) in Mice with Upregulated Opioid System Activity","volume":"326","author":"Lesniak","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Boeuf, B., Poirier, V., Gauvin, F., Guerguerian, A.-M., Roy, C., Farrell, C., and Lacroix, J. (2003). Naloxone for Shock. Cochrane Database Syst. Rev.","DOI":"10.1002\/14651858.CD004443"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1097\/00000441-198508000-00005","article-title":"Severe Hypertension Induced by Naloxone","volume":"290","author":"Levin","year":"1985","journal-title":"Am. J. Med. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1161\/HYPERTENSIONAHA.118.11800","article-title":"Hypertension Is Predicted by Both Large and Small Artery Disease","volume":"73","author":"Kario","year":"2019","journal-title":"Hypertension"},{"key":"ref_33","first-page":"91","article-title":"Kappa-Opioid Receptor Stimulation Contributes to Aortic Artery Dilation through Activation of K(ATP) Channel in the Rats","volume":"55","author":"Pei","year":"2003","journal-title":"Acta Physiol. Sin."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0167-5273(98)00035-7","article-title":"v Delta2 Opioid Receptor Subtype on Human Vascular Endothelium Uncouples Morphine Stimulated Nitric Oxide Release","volume":"64","author":"Stefano","year":"1998","journal-title":"Int. J. Cardiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1161\/01.RES.76.4.536","article-title":"Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions","volume":"76","author":"Noris","year":"1995","journal-title":"Circ. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1161\/hh2301.100806","article-title":"Shear stress regulates endothelial nitric oxide synthase expression through c-Src by divergent signaling pathways","volume":"89","author":"Davis","year":"2001","journal-title":"Circ. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1161\/01.HYP.0000164571.77710.19","article-title":"Angiotensin Type 2 Receptor-Mediated Phosphorylation of eNOS in the Aortas of Mice With 2-Kidney, 1-Clip Hypertension","volume":"45","author":"Hiyoshi","year":"2005","journal-title":"Hypertension"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1111\/bph.14583","article-title":"1,2,3,4,6-Penta-O-Galloyl-\u03b2-d-Glucose Modulates Perivascular Inflammation and Prevents Vascular Dysfunction in Angiotensin II-Induced Hypertension","volume":"176","author":"Mikolajczyk","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1007\/s003930170003","article-title":"Nociception, Pain, and Antinociception: Current Concepts","volume":"60","author":"Riedel","year":"2001","journal-title":"Zeitschrift f\u00fcr Rheumatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"31","DOI":"10.3389\/fnmol.2014.00031","article-title":"Guanylate Cyclase-C\/CGMP: An Emerging Pathway in the Regulation of Visceral Pain","volume":"7","author":"Hannig","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0014-2999(02)02275-6","article-title":"The \u03ba-Opioid Agonist (\u00b1)-Bremazocine Elicits Peripheral Antinociception by Activation of the l-Arginine\/Nitric Oxide\/Cyclic GMP Pathway","volume":"454","author":"Amarante","year":"2002","journal-title":"Eur. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0014-2999(97)01399-X","article-title":"Evidence for the Involvement of the Nitric Oxide-CGMP Pathway in the Antinociception of Morphine in the Formalin Test","volume":"340","author":"Rufino","year":"1997","journal-title":"Eur. J. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.lfs.2005.04.032","article-title":"\u03b4-Opioid Receptor Agonist SNC80 Elicits Peripheral Antinociception via \u03941 and \u03942 Receptors and Activation of the L-Arginine\/Nitric Oxide\/Cyclic GMP Pathway","volume":"78","author":"Pacheco","year":"2005","journal-title":"Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0014-2999(00)00361-7","article-title":"Sildenafil Produces Antinociception and Increases Morphine Antinociception in the Formalin Test","volume":"400","year":"2000","journal-title":"Eur. J. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1080\/00952990902825389","article-title":"Morphine-Induced Changes of Adenylate and Guanylate Cyclase in Locus Ceruleus, Periaqueductal Gray, and Substantia Nigra in Rats","volume":"35","author":"Shijun","year":"2009","journal-title":"Am. J. Drug Alcohol Abus."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/4179\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:49:19Z","timestamp":1760161759000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/4179"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,17]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22084179"],"URL":"https:\/\/doi.org\/10.3390\/ijms22084179","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,17]]}}}