{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T20:36:25Z","timestamp":1793306185408,"version":"4.5.0"},"reference-count":62,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T00:00:00Z","timestamp":1730851200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Opioid drugs are potent analgesics that carry the risk of respiratory side effects due to actions on <jats:italic>\u03bc<\/jats:italic>\u2010opioid receptors (MORs) in brainstem regions that control respiration. Substance P is encoded by the <jats:italic>Tac1<\/jats:italic> gene and is expressed in neurons regulating breathing, nociception, and locomotion. <jats:italic>Tac1\u2010<\/jats:italic>positive cells also express MORs in brainstem regions mediating opioid\u2010induced respiratory depression. We determined the role of <jats:italic>Tac1<\/jats:italic>\u2010positive cells in mediating the respiratory effects of opioid drugs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>In situ hybridization was used to determine <jats:italic>Oprm1<\/jats:italic> mRNA expression (gene encoding MORs) in <jats:italic>Tac1\u2010<\/jats:italic>positive cells in regions regulating respiratory depression by opioid drugs. Conditional knockout mice lacking functional MORs in <jats:italic>Tac1\u2010<\/jats:italic>positive cells were produced and the respiratory and locomotor responses to the opioid analgesic fentanyl were assessed using whole\u2010body plethysmography. A tail immersion assay was used to assess the antinociceptive response to fentanyl.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p><jats:italic>Oprm1<\/jats:italic> mRNA was highly expressed (&gt;80%) in subpopulations of <jats:italic>Tac1\u2010<\/jats:italic>positive cells in the preB\u00f6tzinger Complex, nucleus tractus solitarius, and K\u00f6lliker\u2013Fuse\/lateral parabrachial region. Conditionally knocking out MORs in <jats:italic>Tac1\u2010<\/jats:italic>positive cells abolished the effects of fentanyl on respiratory rate, relative tidal volume, and relative minute ventilation compared with control mice. Importantly, the antinociceptive response of fentanyl was eliminated in mice lacking functional MORs in <jats:italic>Tac1\u2010<\/jats:italic>positive cells, whereas locomotor effects induced by fentanyl were preserved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Our findings suggest that <jats:italic>Tac1\u2010<\/jats:italic>positive cells mediate the respiratory depressive and antinociceptive effects of the opioid fentanyl, providing important insights for the development of pain therapies with reduced risk of respiratory side effects.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17369","type":"journal-article","created":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T06:44:08Z","timestamp":1730961848000},"page":"1059-1074","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mu\u2010opioid receptors in tachykinin\u20101\u2010positive cells mediate the respiratory and antinociceptive effects of the opioid fentanyl"],"prefix":"10.1111","volume":"182","author":[{"given":"Andreea","family":"Furdui","sequence":"first","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael's Hospital  Toronto Ontario Canada"},{"name":"Institute of Medical Science, Faculty of Medicine University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"da Silveira Scarpellini","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael's Hospital  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaspard","family":"Montandon","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael's Hospital  Toronto Ontario Canada"},{"name":"Institute of Medical Science, Faculty of Medicine University of Toronto  Toronto Ontario Canada"},{"name":"Division of Respirology, Department of Medicine, Faculty of Medicine University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,6]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.20-11-04345.2000"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15538"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0003-2697(03)00465-2"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36603-z"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52694"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2011.12.041"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.81119"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00757.x"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00450.2006"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/32897"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-080317-061522"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14153"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00284"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abh4272"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1431"},{"key":"e_1_2_13_17_1","volume-title":"The mouse brain in stereotaxic coordinates","author":"Franklin K. 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