{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T16:41:43Z","timestamp":1773679303140,"version":"3.50.1"},"reference-count":50,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2009,2,2]],"date-time":"2009-02-02T00:00:00Z","timestamp":1233532800000},"content-version":"vor","delay-in-days":1859,"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":[[2004,1]]},"abstract":"<jats:p>\n                    <jats:list list-type=\"explicit-label\">\n                      <jats:list-item>\n                        <jats:p>\n                          Tolerance to opioids frequently follows repeated drug administration and affects the clinical utility of these analgesics. Studies in simple cellular systems have demonstrated that prolonged activation of opioid receptors produces homologous receptor desensitization by G\u2010protein receptor kinase mediated receptor phosphorylation and subsequent\n                          <jats:italic>\u03b2<\/jats:italic>\n                          \u2010arrestin binding. To define the role of this regulatory mechanism in the control of the electrophysiological and behavioral responses to opioids, we used mice having a targeted disruption of the G\u2010protein receptor kinase 3 (GRK3) gene.\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Mice lacking GRK3 did not differ from wild\u2010type littermates neither in their response latencies to noxious stimuli on the hot\u2010plate test nor in their acute antinociceptive responses to fentanyl or morphine.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>\n                          Tolerance to the electrophysiological response to the opioid fentanyl, measured\n                          <jats:italic>in vitro<\/jats:italic>\n                          in the hippocampus, was blocked by GRK3 deletion. In addition, tolerance to the antinociceptive effects of fentanyl was significantly reduced in GRK3 knockouts compared to wild\u2010type littermate controls.\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>\n                          Tolerance to the antinociceptive effects of morphine was not affected by GRK3 deletion although morphine tolerance in hippocampal slices from GRK3 knockout mice was significantly inhibited. Tolerance developed more slowly\n                          <jats:italic>in vitro<\/jats:italic>\n                          to morphine than fentanyl supporting previous work in\n                          <jats:italic>in vitro<\/jats:italic>\n                          systems showing a correlation between agonist efficacy and GRK3\u2010mediated desensitization.\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>The results of these studies suggest that GRK3\u2010mediated mechanisms are important components of both electrophysiologic and behavioral opioid tolerance. Fentanyl, a high efficacy opioid, more effectively produced GRK3\u2010dependent effects than morphine, a low efficacy agonist.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>British Journal of Pharmacology<\/jats:italic>\n                    (2004)\n                    <jats:bold>141<\/jats:bold>\n                    , 55\u201364. doi:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0705595\">10.1038\/sj.bjp.0705595<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1038\/sj.bjp.0705595","type":"journal-article","created":{"date-parts":[[2004,1,7]],"date-time":"2004-01-07T08:53:00Z","timestamp":1073465580000},"page":"55-64","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["G\u2010protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal"],"prefix":"10.1111","volume":"141","author":[{"given":"Gregory W","family":"Terman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenzhen","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young\u2010Pyo","family":"Cheong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet","family":"Lowe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc G","family":"Caron","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J","family":"Lefkowitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Chavkin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,2,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.34.23802"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1997.69062405.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"3893","DOI":"10.1016\/S0021-9258(18)69009-X","article-title":"Beta\u2010adrenergic receptor kinase activity of partial agonists for stimulation of adenylate cyclase correlates with ability to promote receptor phosphorylation","volume":"263","author":"BENOVIC J.L.","year":"1988","journal-title":"J. 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