{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T15:51:49Z","timestamp":1784044309604,"version":"3.55.0"},"reference-count":26,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":2585,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2002,1]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha<jats:sub>2<\/jats:sub>\u2010adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine\/ketamine\u2010induced anaesthesia. We further characterized this latter effect since it appears to reflect the emetic potential of PDE4 inhibitors.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>, i.m.) and ketamine (10\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>, i.m.) PMNPQ (i.e. 6\u2010(4\u2010pyridylmethyl)\u20108\u2010(3\u2010nitrophenyl)quinoline) \u2003\u2013\u2003 PDE4 inhibitor: 0.01\u2003\u2013\u20033\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>), like MK\u2010912 (alpha<jats:sub>2<\/jats:sub>\u2010adrenoceptor antagonist: 0.01\u2003\u2013\u20033\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>), dose\u2010dependently reduced the duration of anaesthesia. In contrast, vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor), milrinone (PDE3 inhibitor) and zaprinast (PDE5 inhibitor) had no significant effect at the doses tested (1\u2003\u2013\u200310\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>). Analysis of plasma and cerebrospinal fluid (CSF) of treated animals confirmed the absorption and distribution to the brain of the inactive inhibitors.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Neither MK\u2010912 (3\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>) nor PMNPQ (0.1\u2003\u2013\u20031\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>) altered the duration of anaesthesia induced via a non\u2010alpha<jats:sub>2<\/jats:sub>\u2010adrenoceptor pathway (sodium pentobarbitone 50\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>, i.p.)<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Central NK<jats:sub>1<\/jats:sub> receptors are involved in PDE4 inhibitor\u2010induced emesis. Consistently, [sar<jats:sup>9<\/jats:sup>, Met(O<jats:sub>2<\/jats:sub>)<jats:sup>11<\/jats:sup>]\u2010substance P (NK<jats:sub>1<\/jats:sub> receptor agonist, 6\u2003\u03bcg\u2003i.c.v.) reduced the duration of anaesthesia induced by xylazine\/ketamine.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In summary, this model is functionally coupled to PDE4, specific to alpha<jats:sub>2<\/jats:sub>\u2010adrenoceptors and relevant to PDE4 inhibitor\u2010induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2002) <jats:bold>135<\/jats:bold>, 113\u2013118; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0704457\">10.1038\/sj.bjp.0704457<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0704457","type":"journal-article","created":{"date-parts":[[2006,6,7]],"date-time":"2006-06-07T19:20:37Z","timestamp":1149708037000},"page":"113-118","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":107,"title":["Assessing the emetic potential of PDE4 inhibitors in rats"],"prefix":"10.1111","volume":"135","author":[{"given":"A","family":"Robichaud","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Savoie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P B","family":"Stamatiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Lachance","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Jolicoeur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Rasori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C C","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,1,29]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"113","volume-title":"Emesis in anti\u2010cancer therapy","author":"ANDREWS P.L.R.","year":"1993"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0702387"},{"key":"e_1_2_7_4_1","first-page":"1046","article-title":"Inhibition of adenylate cyclase in the locus coeruleus mediates the hypnotic response to an alpha2\u2010adrenoceptor2 agonist in the rat","volume":"263","author":"CORREA\u2010SALES C.","year":"1992","journal-title":"J. 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