Intranasal Leptin as A Novel Treatment of Opioid-Induced Respiratory Depression

与阿片类药物相关的主要死亡原因是阿片类药物引起的呼吸抑制(OIRD)。几个 一系列证据表明，在阿片类药物治疗期间，复发性咽部梗阻和呼吸道通畅丧失 暴露是OIRD的一个额外和主要的风险。新的治疗药物的识别和验证- OIRD的解毒剂，不会逆转阿片类药物介导的有益镇痛，也不会导致急性 戒断症状，是迫切需要的。我们已经证明了一种脂肪细胞产生的荷尔蒙瘦素，它 抑制食欲和提高代谢率，还上调对睡眠和呼吸的控制 治疗阻塞性睡眠呼吸暂停(OSA)。虽然肥胖的人类和DIO小鼠对 瘦素，抵抗瘦素的呼吸作用发生在血脑屏障(BBB)水平，可以 如果瘦素被鼻内给药(IN)，使大脑暴露于激素，则可避免。我们的 初步数据表明：(1)吗啡抑制舌下运动神经元(HMN)，诱导OIRD和OSA 在小鼠中；(2)瘦素可以逆转OIRD和OSA；(3)瘦素在体外逆转阿片类药物对HMN的抑制； 瘦素中的瘦素不会减弱止痛作用。我们的总体假设是OIRD可以通过鼻内途径减弱。 注射瘦素，通过恢复呼吸刺激呼吸和增加上呼吸道通畅 HMN活性在维持镇痛的同时无急性戒断。我们将在Lean中测试我们的假设 和DIO雄性和雌性小鼠。特定目标1将验证瘦素途径作为治疗OIRD的靶点。我们 假设In Leptin将逆转(A)OIRD和阿片类药物诱导的OSA；(B)阿片类药物诱导的抑制 高碳酸血症和低氧化疗敏感性；以及(C)上呼吸道塌陷性以剂量依赖的方式。 特定目标2将检查IN Leptin在镇痛和急性阿片类药物戒断中的作用。我们假设 瘦素不会(A)减少止痛，(B)也不会导致急性阿片类药物戒断。《特定目标3》将与 胰岛素、瘦素不同剂型对OIRD的影响具体地说，我们将测试(A)正常情况下制备的瘦素 生理盐水(NS)；(B)十四烷基麦芽糖苷(TDM)；(C)牛磺酸二氢呋喃二钠(STDHF)；(D) 溶血磷脂酰胆碱(LPC)特定目标4将检查瘦素的药代动力学。我们将发展 有助于临床翻译和测量效果的药代动力学/药效学关系 In Leptin对(A)瘦素输送到大脑不同部位；(B)激活Leptin信号通路 C)脑脊液和血浆中瘦素出现的时间进程。特定的 目标5将通过检测3到30倍有效瘦素的作用来检测IN Leptin的毒性 剂量：(A)心血管系统(血压、心率)；(B)内分泌系统(葡萄糖、胰岛素水平)； (C)脑病理；(D)免疫反应(抗瘦素抗体)。我们建议在瘦素中将被指示为 在高危人群中预防OIRD：1)中重度OSA患者需要阿片类止痛；2) 慢性阿片类药物使用者需要大剂量阿片类药物来控制疼痛。

The primary cause of death associated with opioids is opioid-induced respiratory depression (OIRD). Several lines of evidence suggest that recurrent pharyngeal obstruction and loss of airway patency during opioid exposure is an additional and major risk in OIRD. The identification and validation of new therapeutic agents- antidotes for OIRD, which would not reverse the beneficial opioid-mediated analgesia, or cause acute withdrawal symptoms, is urgently needed. We have shown that an adipocyte-produced hormone leptin, which suppresses appetite and increases metabolic rate, also up-regulates control of breathing during sleep and treats obstructive sleep apnea (OSA). While obese humans and DIO mice are resistant to metabolic effects of leptin, resistance to the respiratory effects of leptin occurs at the blood brain barrier (BBB) level and can be circumvented if leptin is administered intranasally (IN), which enables brain exposure to the hormone. Our preliminary data show that: (1) morphine inhibits hypoglossal motoneurons (HMN) and induces OIRD and OSA in mice; (2) IN leptin can reverse OIRD and OSA; (3) leptin reverses opioid-induced HMN inhibition in vitro; (4) IN leptin does not diminish analgesia. Our overall hypothesis is that OIRD can be attenuated by intranasal administration of leptin, which stimulates breathing and increases upper airway patency by restoring HMN activity without acute withdrawal while maintaining analgesia. We will test our hypothesis in lean and DIO male and female mice. Specific Aim 1 will validate the leptin pathway as a target to treat OIRD. We hypothesize that IN leptin will reverse (A) OIRD and opioid-induced OSA; (B) opioid-induced suppression of hypercapnic and hypoxic chemosensitivity; and (C) upper airway collapsibility in a dose-dependent manner. Specific Aim 2 will examine effects of IN leptin on analgesia and acute opioid withdrawal. We hypothesize that leptin will not (A) decrease analgesia nor (B) induce acute opioid withdrawal. Specific Aim 3 will compare effects of different formulations of IN leptin on OIRD. Specifically, we will test leptin prepared in (A) normal saline (NS); (B) tetradecylmaltoside (TDM); (C) sodium taurodihydrofusidate (STDHF); (D) lysophosphatidylcholine (LPC). Specific Aim 4 will examine IN leptin pharmacokinetics. We will develop pharmacokinetic/pharmacodynamics relationships that could aid in clinical translation and measure the effect of IN leptin on (A) leptin delivery to the different parts of the brain; (B) activation of the leptin signaling pathway in the different parts of the brain; and C) the time course of leptin appearance in CSF and plasma. Specific Aim 5 will examine toxicity of IN leptin by examining effects of IN leptin at 3 to 30 fold multiple of the effective dose on (A) cardiovascular system (blood pressure, heart rate); (B) endocrine system (glucose, insulin levels); (C) brain pathology; (D) immune response (anti-leptin antibody). We propose that IN leptin will be indicated to prevent OIRD in high risk populations: 1) patients with moderate-severe OSA requiring opioid analgesia; 2) chronic opioid users requiring high dose opioids for pain control.