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Given the presence of opioid receptors (MORs) and mGluR\n                    <jats:sub>5<\/jats:sub>\n                    in glia and neurons, together with reports that suggest coexpressed MOR\/mGluR\n                    <jats:sub>5<\/jats:sub>\n                    receptors in cultured cells associate as a heteromer, the possibility that such a heteromer could be a target in vivo was addressed by the design and synthesis of a series of bivalent ligands that contain mu opioid agonist and mGluR\n                    <jats:sub>5<\/jats:sub>\n                    antagonist pharmacophores linked through spacers of varying length (10\u201324 atoms). The series was evaluated for antinociception using the tail-flick and von Frey assays in mice pretreated with lipopolysaccharide (LPS) or in mice with bone cancer. In LPS-pretreated mice, MMG22 (4c, 22-atom spacer) was the most potent member of the series (intrathecal ED\n                    <jats:sub>50<\/jats:sub>\n                    \u223c9 fmol per mouse), whereas in untreated mice its ED\n                    <jats:sub>50<\/jats:sub>\n                    was more than three orders of magnitude higher. As members of the series with shorter or longer spacers have \u2265500-fold higher ED\n                    <jats:sub>50s<\/jats:sub>\n                    in LPS-treated mice, the exceptional potency of MMG22 may be a result of the optimal bridging of protomers in a putative MOR-mGluR\n                    <jats:sub>5<\/jats:sub>\n                    heteromer. The finding that MMG22 possesses a &gt;10\n                    <jats:sup>6<\/jats:sup>\n                    therapeutic ratio suggests that it may be an excellent candidate for treatment of chronic, intractable pain via spinal administration.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1305461110","type":"journal-article","created":{"date-parts":[[2013,6,25]],"date-time":"2013-06-25T00:20:05Z","timestamp":1372119605000},"page":"11595-11599","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":77,"title":["Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception"],"prefix":"10.1073","volume":"110","author":[{"given":"Eyup","family":"Akg\u00fcn","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad I.","family":"Javed","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary M.","family":"Lunzer","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Branden A.","family":"Smeester","sequence":"additional","affiliation":[{"name":"Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Al J.","family":"Beitz","sequence":"additional","affiliation":[{"name":"Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip S.","family":"Portoghese","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,6,24]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2009.02.005"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nucmedbio.2007.07.009"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(01)00767-3"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2007.01.015"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2004.03609.x"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2007.10.007"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2008.12.010"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506627102"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2009.10.045"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm034234f"},{"key":"e_1_3_3_11_2","unstructured":"MJ Lewenstein U Weiss US Patent US2806033. 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