The efficacy of intranasal leptin for opioid-induced respiratory depression depends on sex and obesity state.
The efficacy of intranasal leptin for opioid-induced respiratory depression depends on sex and obesity state.
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鼻内瘦素对阿片类药物诱导的呼吸抑制的功效取决于性别和肥胖状态。
DOI：
10.3389/fphys.2023.1320151
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发表时间：
2023
影响因子：
4
通讯作者：
Polotsky, Vsevolod Y.
中科院分区：
文献类型：
--
作者：
Singer, Michele L.;Shin, Mi-Kyung;Kim, Lenise J.;Freire, Carla;Aung, O.;Pho, Huy;East, Joshua A.;Sgambati, Frank P.;Latremoliere, Alban;Pham, Luu V.;Polotsky, Vsevolod Y.
前言：阿片类药物引起的呼吸抑制(OIRD)是阿片类药物致死的主要原因，肥胖患者尤其易患阻塞性睡眠呼吸暂停(OSA)。反复接触阿片类药物，就像疼痛管理一样，会导致治疗效果减弱和/或需要更大剂量才能保持同样的效果。由于解决反复暴露的负面影响的手段有限，因此至关重要的是开发既能防止阿片类药物导致的死亡又不减少有益的止痛作用的药物。方法：我们假设由于长期使用阿片类药物而导致的OIRD可以通过注射IN Leptin来减轻，同时还可以维持对瘦小鼠和饮食诱导肥胖(DIO)小鼠的镇痛作用。为了验证这一假设，制定了阿片耐受方案，并建立了长期接受吗啡并对吗啡镇痛耐受的小鼠OIRD模型。随后，用气压体积描记仪记录了四个实验组的呼吸：肥胖男性，肥胖女性，瘦男性，以及急性注射IN Leptin后的瘦女性。呼吸数据与动脉血气测量相辅相成。采用可操作性行为分析方法，观察IN-Leptin对吗啡镇痛效应的影响。结果：急性应用IN-Leptin可显着减轻DIO雄性小鼠的OIRD，呼吸暂停指数和呼吸暂停时间分别减少58.9%和60.1%。瘦素对瘦小的小鼠无效。血气测定证实了IN-Leptin预防DIO雄性小鼠呼吸性酸中毒的有效性。然而，IN Leptin对瘦小鼠并不有效，而且似乎会加剧DIO雌性小鼠的酸碱失衡。此外，吗啡引起的体温厌恶完全消失，这种厌恶不能被鼻腔内注射的瘦素减轻，这表明IN瘦素不会减少吗啡的镇痛作用。讨论：在不影响镇痛的情况下，瘦素能有效治疗吗啡耐受DIO雄性小鼠的OIRD。相比之下，IN Leptin对瘦小鼠，无论是雌性还是DIO雌性小鼠都没有影响。动脉血气数据与呼吸机结果一致，表明IN Leptin仅在DIO雄性小鼠中逆转了吗啡诱导的呼吸性酸中毒，而在其他小鼠组中没有。最后，一项高碳酸血症敏感性研究显示，IN Leptin仅在DIO雄性小鼠高碳酸血症条件下挽救了每分钟的通气量，这表明对IN Leptin的不同反应可归因于性别和肥胖状况的不同瘦素敏感性。
Introduction: 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. Methods: 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. Results: 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. Discussion: 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.
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影响因子：
5.6
作者：
Amorim MR;Dergacheva O;Fleury-Curado T;Pho H;Freire C;Mendelowitz D;Branco LGS;Polotsky VY
通讯作者：
Polotsky VY
影响因子：
3.3
作者：
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影响因子：
8.8
作者：
Do J;Chang Z;Sekerková G;McCrimmon DR;Martina M
通讯作者：
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影响因子：
3.3
作者：
Kim, Lenise J.;Alexandre, Chloe;Pham, Luu V.
通讯作者：
Pham, Luu V.
影响因子：
--
作者：
Inyushkina, E M;Merkulova, N A;Inyushkin, A N
通讯作者：
Inyushkin, A N