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Although many brainstem regions have been shown to regulate opioid-induced respiratory depression, the types of neurons involved have not been identified. Somatostatin is a major neuropeptide found in brainstem circuits regulating breathing, but it is unknown whether somatostatin-expressing circuits regulate respiratory depression by opioids. We examined the coexpression of<jats:italic>Sst<\/jats:italic>(gene encoding somatostatin) and<jats:italic>Oprm1<\/jats:italic>(gene encoding MORs) mRNAs in brainstem regions involved in respiratory depression. Interestingly,<jats:italic>Oprm1<\/jats:italic>mRNA expression was found in the majority (&gt;50%) of<jats:italic>Sst<\/jats:italic>-expressing cells in the preB\u00f6tzinger Complex, the nucleus tractus solitarius, the nucleus ambiguus, and the K\u00f6lliker\u2013Fuse nucleus. We then compared respiratory responses to fentanyl between wild-type and<jats:italic>Oprm1<\/jats:italic>full knock-out mice and found that the lack of MORs prevented respiratory rate depression from occurring. Next, using transgenic knock-out mice lacking functional MORs specifically in<jats:italic>Sst<\/jats:italic>-expressing cells, we compared respiratory responses to fentanyl between control and the conditional knock-out mice. We found that respiratory rate depression by fentanyl was preserved when MORs were deleted only in<jats:italic>Sst<\/jats:italic>-expressing cells. Our results show that despite coexpression of<jats:italic>Sst<\/jats:italic>and<jats:italic>Oprm1<\/jats:italic>in respiratory circuits and the importance of somatostatin-expressing cells in the regulation of breathing, these cells do not mediate opioid-induced respiratory rate depression. Instead, MORs found in respiratory cell populations other than<jats:italic>Sst<\/jats:italic>-expressing cells likely contribute to the respiratory effects of fentanyl.<\/jats:p>","DOI":"10.1523\/eneuro.0035-23.2023","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T17:50:12Z","timestamp":1687801812000},"page":"ENEURO.0035-23.2023","source":"Crossref","is-referenced-by-count":20,"title":["Fentanyl-Induced Respiratory Depression and Locomotor Hyperactivity Are Mediated by \u03bc-Opioid Receptors Expressed in Somatostatin-Negative Neurons"],"prefix":"10.1523","volume":"10","author":[{"given":"Andreea","family":"Furdui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"da Silveira Scarpellini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaspard","family":"Montandon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2023,6,26]]},"reference":[{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-2697(03)00465-2"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52694"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.3","doi-asserted-by":"publisher","DOI":"10.1002\/cne.902620408"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.4","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1111\/j.1476-5381.2010.00757.x","article-title":"Increased morphine analgesia and reduced side effects in mice lacking the tac1 gene","volume":"160","year":"2010","journal-title":"Br J Pharmacol"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.5","doi-asserted-by":"publisher","DOI":"10.1002\/cne.23846"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.6","doi-asserted-by":"crossref","first-page":"e0153187","DOI":"10.1371\/journal.pone.0153187","article-title":"Activation of brainstem pro-opiomelanocortin neurons produces opioidergic analgesia, bradycardia and bradypnoea","volume":"11","year":"2016","journal-title":"PLoS One"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(02)01812-5"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.07.003"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.9","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200105000-00021"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.10","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181c38c25"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0143-4179(92)90147-O","article-title":"Distribution of somatostatin-28 (1-12) in the cat brainstem: an immunocytochemical study","volume":"21","year":"1992","journal-title":"Neuropeptides"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.12","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1113\/JP282002","article-title":"Phase- and state-dependent modulation of breathing pattern by preB\u00f6tzinger complex somatostatin expressing neurons","volume":"600","year":"2022","journal-title":"J Physiol"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.13","doi-asserted-by":"crossref","first-page":"ENEURO.0487-21.2022","DOI":"10.1523\/ENEURO.0487-21.2022","article-title":"The Contributions of Mu-Opioid Receptors on Glutamatergic and GABAergic Neurons to Analgesia Induced by Various Stress Intensities","volume":"9","year":"2022","journal-title":"eNeuro"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.14","doi-asserted-by":"publisher","DOI":"10.1139\/cjpp-76-10-11-945"},{"key":"2023062810500557000_10.6.ENEURO.0035-23.2023.15","unstructured":"Franklin KBJ , Paxinos G (2008) The mouse brain in stereotaxic coordinates, Ed 3. 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