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Most clinically used analgesics target the \u03bc opioid receptor whose activation results in adverse effects like respiratory depression, addiction and abuse liability. Various approaches have been used by the field to separate receptor\u2010mediated analgesic actions from adverse effects. These include biased agonism, opioids targeting multiple receptors, allosteric modulators, heteromers and splice variants of the \u03bc receptor. This review will focus on the current status of the field and some upcoming targets of interest that may lead to a safer next generation of analgesics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LINKED ARTICLES<\/jats:title>\n                    <jats:p>\n                      This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v180.7\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v180.7\/issuetoc<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.15760","type":"journal-article","created":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T19:54:27Z","timestamp":1637956467000},"page":"975-993","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Strategies towards safer opioid analgesics\u2014A review of old and upcoming targets"],"prefix":"10.1111","volume":"180","author":[{"given":"Balazs R.","family":"Varga","sequence":"first","affiliation":[{"name":"Center for Clinical Pharmacology University of Health Sciences and Pharmacy in St. Louis and Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4173-7362","authenticated-orcid":false,"given":"John M.","family":"Streicher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2931-3823","authenticated-orcid":false,"given":"Susruta","family":"Majumdar","sequence":"additional","affiliation":[{"name":"Center for Clinical Pharmacology University of Health Sciences and Pharmacy in St. Louis and Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,1,21]]},"reference":[{"key":"e_1_2_14_2_1","first-page":"299","article-title":"Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice","volume":"258","author":"Abdelhamid E. 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