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As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced<jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>\u2010mediated antinociception.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We used a tail withdrawal assay in<jats:styled-content style=\"fixed-case\">C<\/jats:styled-content>57<jats:styled-content style=\"fixed-case\">B<\/jats:styled-content>l\/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at<jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating<jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>\u2010mediated antinociception.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Etorphine, a potent agonist at all four opioid receptors, was not anti\u2010nociceptive in<jats:styled-content style=\"fixed-case\">MOP<\/jats:styled-content>knockout (<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content>) mice, although etorphine is an efficacious<jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>receptor agonist and specific<jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>receptor agonists remain analgesic in<jats:styled-content style=\"fixed-case\">MOP KO<\/jats:styled-content>mice. As<jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>receptor agonists are aversive, we considered<jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>\u2010mediated antinociception might be a form of stress\u2010induced analgesia that is blocked by the anxiolytic effects of<jats:styled-content style=\"fixed-case\">DOP<\/jats:styled-content>receptor agonists. In support of this hypothesis, pretreatment with the<jats:styled-content style=\"fixed-case\">DOP<\/jats:styled-content>antagonist, naltrindole (10\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>), unmasked etorphine (3\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>) antinociception in<jats:styled-content style=\"fixed-case\">MOP KO<\/jats:styled-content>mice. Further, in wild\u2010type mice,<jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>\u2010mediated antinociception by systemic<jats:styled-content style=\"fixed-case\">U<\/jats:styled-content>50,488<jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>(10\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>) was blocked by pretreatment with the<jats:styled-content style=\"fixed-case\">DOP<\/jats:styled-content>agonist<jats:styled-content style=\"fixed-case\">SNC<\/jats:styled-content>80 (5\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>) and diazepam (1\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Systemic<jats:styled-content style=\"fixed-case\">DOP<\/jats:styled-content>receptor agonists blocked systemic<jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>antinociception, and these results identify<jats:styled-content style=\"fixed-case\">DOP<\/jats:styled-content>receptor agonists as potential agents for reversing stress\u2010driven addictive and depressive behaviours mediated through<jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>receptor activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/dx.doi.org\/10.1111\/bph.2015.172.issue-2\">http:\/\/dx.doi.org\/10.1111\/bph.2015.172.issue-2<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12810","type":"journal-article","created":{"date-parts":[[2014,6,13]],"date-time":"2014-06-13T07:05:02Z","timestamp":1402643102000},"page":"691-703","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Anti\u2010nociception mediated by a \u03ba opioid receptor agonist is blocked by a \u03b4 receptor agonist"],"prefix":"10.1111","volume":"172","author":[{"given":"A M W","family":"Taylor","sequence":"first","affiliation":[{"name":"University of California Los Angeles CA USA"},{"name":"University of California Irvine Irvine CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K 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