{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:24:27Z","timestamp":1787027067400,"version":"build-2736575974"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T00:00:00Z","timestamp":1702425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>\n                    <jats:bold>Introduction:<\/jats:bold>\n                    Opioid-induced respiratory depression (OIRD) is the primary cause of death associated with opioids and individuals with obesity are particularly susceptible due to comorbid obstructive sleep apnea (OSA). Repeated exposure to opioids, as in the case of pain management, results in diminished therapeutic effect and\/or the need for higher doses to maintain the same effect. With limited means to address the negative impact of repeated exposure it is critical to develop drugs that prevent deaths induced by opioids without reducing beneficial analgesia.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    We hypothesized that OIRD as a result of chronic opioid use can be attenuated by administration of IN leptin while also maintaining analgesia in both lean mice and mice with diet-induced obesity (DIO) of both sexes. To test this hypothesis, an opioid tolerance protocol was developed and a model of OIRD in mice chronically receiving morphine and tolerant to morphine analgesia was established. Subsequently, breathing was recorded by barometric plethysmography in four experimental groups: obese male, obese female, lean male, and lean female following acute administration of IN leptin. Respiratory data were complemented with measures of arterial blood gas. Operant behavioral assays were used to determine the impact of IN leptin on the analgesic efficacy of morphine.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    Acute administration of IN leptin significantly attenuated OIRD in DIO male mice decreasing the apnea index by 58.9% and apnea time by 60.1%. In lean mice leptin was ineffective. Blood gas measures confirmed the effectiveness of IN leptin for preventing respiratory acidosis in DIO male mice. However, IN leptin was not effective in lean mice of both sexes and appeared to exacerbate acid-base disturbances in DIO female mice. Additionally, morphine caused a complete loss of temperature aversion which was not reduced by intranasal leptin indicating IN leptin does not decrease morphine analgesia.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Discussion:<\/jats:bold>\n                    IN leptin effectively treated OIRD in morphine-tolerant DIO male mice without impacting analgesia. In contrast, IN leptin had no effect in lean mice of either sex or DIO female mice. The arterial blood gas data were consistent with ventilatory findings showing that IN leptin reversed morphine-induced respiratory acidosis only in DIO male mice but not in other mouse groups. Finally, a hypercapnic sensitivity study revealed that IN leptin rescued minute ventilation under hypercapnic conditions only in DIO male mice, which suggests that differential responses to IN leptin are attributable to different leptin sensitivities depending on sex and the obesity status.\n                  <\/jats:p>","DOI":"10.3389\/fphys.2023.1320151","type":"journal-article","created":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T00:30:01Z","timestamp":1702427401000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["The efficacy of intranasal leptin for opioid-induced respiratory depression depends on sex and obesity state"],"prefix":"10.3389","volume":"14","author":[{"given":"Michele L.","family":"Singer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Kyung","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenise J.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Freire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O","family":"Aung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huy","family":"Pho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua A.","family":"East","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank P.","family":"Sgambati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alban","family":"Latremoliere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luu V.","family":"Pham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vsevolod Y.","family":"Polotsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,13]]},"reference":[{"key":"B1","unstructured":"Drug overdose death rates [WWW Document]2023"},{"key":"B2","doi-asserted-by":"publisher","first-page":"935","DOI":"10.3390\/biom13060935","article-title":"Hyperactivity in mice induced by opioid agonists with partial intrinsic efficacy and biased agonism administered alone and in combination with morphine","volume":"13","author":"Acevedo-Canabal","year":"2023","journal-title":"Biomolecules"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1378\/chest.10-1108","article-title":"Perioperative management of obstructive sleep apnea","volume":"138","author":"Adesanya","year":"2010","journal-title":"Chest"},{"key":"B4","doi-asserted-by":"publisher","first-page":"6742","DOI":"10.3390\/ijms22136742","article-title":"The effect of DREADD activation of leptin receptor positive neurons in the nucleus of the solitary tract on sleep disordered breathing","volume":"22","author":"Amorim","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1111\/bph.15580","article-title":"Understanding and countering opioid-induced respiratory depression","volume":"180","author":"Bateman","year":"2021","journal-title":"Br. J. Pharmacol. n\/a"},{"key":"B6","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1164\/rccm.201805-0879OC","article-title":"Intranasal leptin relieves sleep-disordered breathing in mice with diet-induced obesity","volume":"199","author":"Berger","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"14970","DOI":"10.1038\/s41598-020-71804-2","article-title":"Genetic variation regulates opioid-induced respiratory depression in mice","volume":"10","author":"Bubier","year":"2020","journal-title":"Sci. Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1113\/JP276900","article-title":"Leptin acts in the carotid bodies to increase minute ventilation during wakefulness and sleep and augment the hypoxic ventilatory response","volume":"597","author":"Caballero\u2010Eraso","year":"2019","journal-title":"J. Physiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1097\/00000542-198507000-00004","article-title":"Pronounced, episodic oxygen desaturation in the postoperative period: its association with ventilatory pattern and analgesic regimen","volume":"63","author":"Catley","year":"1985","journal-title":"Anesthesiology"},{"key":"B10","unstructured":"CDC WONDER [WWW Document]2023"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1016\/j.celrep.2018.01.006","article-title":"Mechanistic differences in neuropathic pain modalities revealed by correlating behavior with global expression profiling","volume":"22","author":"Cobos","year":"2018","journal-title":"Cell Rep."},{"key":"B12","doi-asserted-by":"publisher","first-page":"108358","DOI":"10.1016\/j.celrep.2020.108358","article-title":"A leptin-mediated neural mechanism linking breathing to metabolism","volume":"33","author":"Do","year":"2020","journal-title":"Cell Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1542\/peds.16.1.81","article-title":"A barometric method for measuring ventilation in newborn infants","volume":"16","author":"Drorbaugh","year":"1955","journal-title":"Pediatrics"},{"key":"B14","doi-asserted-by":"publisher","first-page":"zsy089","DOI":"10.1093\/sleep\/zsy089","article-title":"Sleep-disordered breathing in C57BL\/6J mice with diet-induced obesity","volume":"41","author":"Fleury Curado","year":"2018","journal-title":"Sleep"},{"key":"B15","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1165\/rcmb.2020-0117OC","article-title":"Intranasal leptin prevents opioid-induced sleep-disordered breathing in obese mice","volume":"63","author":"Freire","year":"2020","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1165\/rcmb.2022-0229LE","article-title":"Leptin-loaded extracellular vesicles treat sleep-disordered breathing in mice with obesity","volume":"67","author":"Freire","year":"2022","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1097\/ALN.0b013e31819b5d70","article-title":"Identification of patients at risk for postoperative respiratory complications using a preoperative obstructive sleep","volume":"110","author":"Gali","year":"2009","journal-title":"Apnea Screen. Tool Postanesthesia Care Assess."},{"key":"B18","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.neulet.2017.09.012","article-title":"Leptin status alters buprenorphine-induced antinociception in obese mice with dysfunctional leptin receptors","volume":"660","author":"Glovak","year":"2017","journal-title":"Neurosci. Lett."},{"key":"B19","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1038\/nn0901-927","article-title":"Normal breathing requires preB\u00f6tzinger complex neurokinin-1 receptor-expressing neurons","volume":"4","author":"Gray","year":"2001","journal-title":"Nat. Neurosci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1097\/00000542-200605000-00026","article-title":"Practice guidelines for the perioperative management of patients with obstructive sleep apnea: a report by the American Society of Anesthesiologists Task Force on Perioperative Management of patients with obstructive sleep apnea","volume":"104","author":"Gross","year":"2006","journal-title":"Anesthesiology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1152\/japplphysiol.00818.2011","article-title":"Novel whole body plethysmography system for the continuous characterization of sleep and breathing in a mouse","volume":"112","author":"Hernandez","year":"2012","journal-title":"J. Appl. Physiology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s11055-009-9124-8","article-title":"Respiratory responses to microinjections of leptin into the solitary tract nucleus","volume":"39","author":"Inyushkin","year":"2009","journal-title":"Neurosci. Behav. Physiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1007\/s11055-010-9316-2","article-title":"Mechanisms of the respiratory activity of leptin at the level of the solitary tract nucleus","volume":"40","author":"Inyushkina","year":"2010","journal-title":"Neurosci. Behav. Physiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1152\/japplphysiol.00386.2022","article-title":"Diet-induced obesity leads to sleep fragmentation independently of the severity of sleep-disordered breathing","volume":"133","author":"Kim","year":"2022","journal-title":"J. Appl. Physiology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1093\/sleep\/zsad158","article-title":"The effect of diet-induced obesity on sleep and breathing in female mice","volume":"46","author":"Kim","year":"2023","journal-title":"Sleep"},{"key":"B26","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/s41467-018-08162-1","article-title":"Phosphorylation-deficient G-protein-biased \u03bc-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects","volume":"10","author":"Kliewer","year":"2019","journal-title":"Nat. Commun."},{"key":"B27","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1097\/ACO.0000000000000265","article-title":"Obstructive sleep apnea, pain, and opioids: is the riddle solved?","volume":"29","author":"Lam","year":"2016","journal-title":"Curr. Opin. Anaesthesiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e60600","DOI":"10.1371\/journal.pone.0060600","article-title":"Characteristics of opioid-users whose death was related to opioid-toxicity: a population-based study in ontario, Canada","volume":"8","author":"Madadi","year":"2013","journal-title":"PLOS ONE"},{"key":"B29","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1093\/ije\/dyx127","article-title":"Explaining recent mortality trends among younger and middle-aged White Americans","volume":"47","author":"Masters","year":"2018","journal-title":"Int. J. Epidemiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1113\/jphysiol.2013.261974","article-title":"CrossTalk proposal: the preBotzinger complex is essential for the respiratory depression following systemic administration of opioid analgesics","volume":"592","author":"Montandon","year":"2014","journal-title":"J. Physiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1292","DOI":"10.1523\/JNEUROSCI.4611-10.2011","article-title":"PreBotzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression","volume":"31","author":"Montandon","year":"2011","journal-title":"J. Neurosci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1097\/ALN.0000000000000984","article-title":"G-protein-gated inwardly rectifying potassium channels modulate respiratory depression by opioids","volume":"124","author":"Montandon","year":"2016","journal-title":"Anesthesiology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1728","DOI":"10.1016\/j.clinthera.2013.10.001","article-title":"Pain as the fifth vital sign: exposing the vital need for pain education","volume":"35","author":"Morone","year":"2013","journal-title":"Clin. Ther."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1124\/pr.112.007138","article-title":"Mu opioids and their receptors: evolution of a concept","volume":"65","author":"Pasternak","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"B35","volume-title":"Leptin receptor expression in the dorsomedial hypothalamus stimulates breathing during NREM sleep in <em>db\/db<\/em> mice","author":"Pho","year":"2020"},{"key":"B36","first-page":"472","article-title":"EFFECTS OF NARCOTIC ANALGESICS UPON THE LOCOMOTOR ACTIVITY AND BRAIN CATECHOLAMINE CONTENT OF THE MOUSE","volume":"176","author":"Rethy","year":"1971","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B37","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1126\/science.1683005","article-title":"Pre-b\u00f6tzinger complex: a brainstem region that may generate respiratory rhythm in mammals","volume":"254","author":"Smith","year":"1991","journal-title":"Science"},{"key":"B38","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1093\/bja\/aex341","article-title":"Death or near-death in patients with obstructive sleep apnoea: a compendium of case reports of critical complications","volume":"119","author":"Subramani","year":"2017","journal-title":"Br. J. Anaesth."},{"key":"B39","doi-asserted-by":"publisher","first-page":"221","DOI":"10.2105\/AJPH.2007.131714","article-title":"The promotion and marketing of oxycontin: commercial triumph, public health tragedy","volume":"99","author":"Van Zee","year":"2009","journal-title":"Am. J. Public Health"},{"key":"B40","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.neuropharm.2019.03.023","article-title":"Opioid-like antinociceptive and locomotor effects of emerging fentanyl-related substances","volume":"151","author":"Varshneya","year":"2019","journal-title":"Neuropharmacology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1016\/j.jpain.2009.02.003","article-title":"Leptin replacement restores supraspinal cholinergic antinociception in leptin-deficient obese mice","volume":"10","author":"Wang","year":"2009","journal-title":"J. Pain"},{"key":"B42","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1080\/08958378.2017.1282065","article-title":"Effects of inhaled aerosolized carfentanil on real-time physiological responses in mice: a preliminary evaluation of naloxone","volume":"29","author":"Wong","year":"2017","journal-title":"Inhal. Toxicol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s12264-021-00742-4","article-title":"A neural circuit mechanism controlling breathing by leptin in the nucleus tractus solitarii","volume":"38","author":"Yu","year":"2021","journal-title":"Neurosci. Bull."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2023.1320151\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T00:30:10Z","timestamp":1702427410000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2023.1320151\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,13]]},"references-count":43,"alternative-id":["10.3389\/fphys.2023.1320151"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2023.1320151","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,13]]},"article-number":"1320151"}}