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In co\u2010administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms. Effects of spironolactone (100 mg\/kg, i.p.), eplerenone (100 mg\/kg, i.p.), chlorothiazide (50 mg\/kg, i.p.) and furosemide (100 mg\/kg, i.p.) were studied on acute oxycodone (0.75 mg\/kg, s.c.)\u2010 and morphine (3 mg\/kg, s.c.)\u2010induced antinociception using tail\u2010flick and hot plate tests in male Sprague Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry. In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system.<\/jats:p>","DOI":"10.1111\/bcpt.12634","type":"journal-article","created":{"date-parts":[[2016,6,17]],"date-time":"2016-06-17T05:37:03Z","timestamp":1466141823000},"page":"38-45","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Do Diuretics have Antinociceptive Actions: Studies of Spironolactone, Eplerenone, Furosemide and Chlorothiazide, Individually and with Oxycodone and Morphine"],"prefix":"10.1111","volume":"120","author":[{"given":"Viljami","family":"Jokinen","sequence":"first","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuomas","family":"Lilius","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jouko","family":"Laitila","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Faculty of Medicine University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikko","family":"Niemi","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Faculty of Medicine University of Helsinki Helsinki Finland"},{"name":"HUSLAB Helsinki University Hospital Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg","family":"Kambur","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eija","family":"Kalso","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine University of Helsinki Helsinki Finland"},{"name":"Division of Pain Medicine Department of Anesthesiology, Intensive Care and Pain Medicine University of Helsinki and Helsinki University Hospital Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pekka","family":"Rauhala","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,7,21]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdr390"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0039897"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2010.08.050"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000000277"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3182700383"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.12.023"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02002628"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1532-2149.2013.00371.x"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00426640"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-10-0472"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra035021"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2006.01.009"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200610000-00027"},{"key":"e_1_2_6_15_1","first-page":"1","article-title":"Human UGT2B7 catalyzes morphine glucuronidation","volume":"25","author":"Coffman BL","year":"1997","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_6_16_1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/S0026-895X(25)09902-X","article-title":"A recombinant phenobarbital\u2010inducible rat liver UDP\u2010glucuronosyltransferase (UDP\u2010glucuronosyltransferase 2B1) stably expressed in V79 cells catalyzes the glucuronidation of morphine, phenols, and carboxylic acids","volume":"45","author":"Pritchard M","year":"1994","journal-title":"Mol Pharmacol"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.108.022087"},{"key":"e_1_2_6_18_1","first-page":"4","article-title":"Guiding principles in the use of animals in toxicology. 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