{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T01:50:38Z","timestamp":1778118638869,"version":"3.51.4"},"reference-count":51,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,1,30]],"date-time":"2009-01-30T00:00:00Z","timestamp":1233273600000},"content-version":"vor","delay-in-days":1247,"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":[[2005,9]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>P2X<jats:sub>3<\/jats:sub>\/P2X<jats:sub>2\/3<\/jats:sub> receptors have emerged as important components of nociception. However, there is limited information regarding the neurochemical systems that are affected by antagonism of the P2X<jats:sub>3<\/jats:sub>\/P2X<jats:sub>2\/3<\/jats:sub> receptor and that ultimately contribute to the ensuing antinociception. In order to determine if the endogenous opioid system is involved in this antinociception, naloxone was administered just prior to the injection of a selective P2X<jats:sub>3<\/jats:sub>\/P2X<jats:sub>2\/3<\/jats:sub> receptor antagonist, A\u2010317491, in rat models of neuropathic, chemogenic, and inflammatory pain.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Naloxone (1\u201310\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>, i.p.), dose\u2010dependently reduced the antinociceptive effects of A\u2010317491 (1\u2013300\u2003<jats:italic>\u03bc<\/jats:italic>mol\u2003kg<jats:sup>\u22121<\/jats:sup>, s.c.) in the CFA model of thermal hyperalgesia and the formalin model of chemogenic pain (2nd phase), but not in the L5\u2013L6 spinal nerve ligation model of neuropathic allodynia. In comparison experiments, the same doses of naloxone blocked or attenuated the actions of morphine (2 or 8\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>, s.c.) in each of these behavioral models.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Injection of a peripheral opioid antagonist, naloxone methiodide (10\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>, i.p.), did not affect A\u2010317491\u2010induced antinociception in the CFA and formalin assays, suggesting that the opioid component of this antinociception occurred within the CNS. Furthermore, this utilization of the central opioid system could be initiated by antagonism of spinal P2X<jats:sub>3<\/jats:sub>\/P2X<jats:sub>2\/3<\/jats:sub> receptors since the antinociceptive actions of intrathecally delivered A\u2010317491 (30\u2003nmol) in the formalin model were reduced by both intrathecally (10\u201350\u2003nmol) and systemically (10\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>, i.p.) administered naloxone.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>This utilization of the opioid system was not specific to A\u2010317491 since suramin\u2010, a nonselective P2X receptor antagonist, induced antinociception was also attenuated by naloxone.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In <jats:italic>in vitro<\/jats:italic> studies, A\u2010317491 (3\u2013100\u2003<jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>) did not produce any agonist response at <jats:italic>\u03b4<\/jats:italic> opioid receptors expressed in NG108\u201015 cells. A\u2010317491 had been previously shown to be inactive at the <jats:italic>\u03ba<\/jats:italic> and <jats:italic>\u03bc<\/jats:italic> opioid receptors. Furthermore, naloxone, at concentrations up to 1\u2003m<jats:sc>M<\/jats:sc>, did not compete for [<jats:sup>3<\/jats:sup>H] A\u2010317491 binding in 1321N1 cells expressing human P2X<jats:sub>3<\/jats:sub> receptors.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Taken together, these results indicate that antagonism of spinal P2X<jats:sub>3<\/jats:sub>\/P2X<jats:sub>2\/3<\/jats:sub> receptors results in an indirect activation of the opioid system to alleviate inflammatory hyperalgesia and chemogenic nociception.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2005) <jats:bold>146<\/jats:bold>, 180\u2013188. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0706346\">10.1038\/sj.bjp.0706346<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0706346","type":"journal-article","created":{"date-parts":[[2005,7,25]],"date-time":"2005-07-25T11:00:21Z","timestamp":1122289221000},"page":"180-188","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Endogenous opioid mechanisms partially mediate P2X<sub>3<\/sub>\/P2X<sub>2\/3<\/sub>\u2010related antinociception in rat models of inflammatory and chemogenic pain but not neuropathic pain"],"prefix":"10.1111","volume":"146","author":[{"given":"Steve","family":"McGaraughty","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prisca","family":"Honore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol 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