Restoring The Mechanical Properties of the Respiratory System as a Treatment of Fentanyl Overdose-Induced Hypoventilation using Kappa Agonists

摘要 μ-阿片激动剂过量与即刻和长期强直性和节律性收缩相关， 吸气和呼气的肌肉，阻碍呼吸运动数小时。这种作用，被称为阿片类药物 引起的胸壁僵硬是导致阿片类药物引起的通气不足致死的关键机制。 μ-阿片诱导的肌肉“僵硬”是由蓝斑的神经元产生的，并且可以被抑制。 κ-阿片受体激动剂，但不是由目前的兴奋剂。我们建议的目的是 证明，在μ阿片受体激动剂芬太尼过量后，κ阿片受体 激动剂1-恢复被动呼吸力学的改变并抑制所产生的高代谢 通过芬太尼诱导的肌肉僵硬，2-防止未镇静大鼠的致命结果。我们将测试纳呋拉芬， 只有市售的κ激动剂，并表明它抵消了芬太尼的镇痛作用， 服药过量如果在啮齿类动物中证实了疗效，我们将在非麻醉的大型动物中进行这些疗效研究。 哺乳动物模型，并将测试静脉内以及鼻内途径。我们的最终目标是获得FDA的批准 对于纳呋拉芬作为μ阿片受体激动剂诱导的通气不足的治疗， 用于从大规模伤亡到阿片类药物中毒的个体受害者的适应症。

ABSTRACT Mu-opioid agonist overdose is associated with immediate and prolonged tetanic and rhythmic contractions of the inspiratory and expiratory muscles that impede respiratory movements for hours. This effect, referred to as opioid induced chest wall rigidity, is a critical mechanism contributing to the lethality of opioid-induced hypoventilation. Mu-opioid-induced muscle “rigidity” is produced by neurons in the locus coeruleus and can be suppressed by kappa-opioid receptor agonists, but not by current ventilatory stimulants. The objective of our proposal is to demonstrate, following an overdose by the mu-opioid receptor agonist fentanyl, that kappa-opioid receptor agonists 1- restore the alteration of passive respiratory mechanics and suppress the hypermetabolism produced by fentanyl induced muscle rigidity, 2- prevent a fatal outcome in unsedated rats. We will test nalfurafine, the only commercially available kappa agonist, and show that it counteracts the ventilatory effects of a fentanyl overdose. If efficacy is demonstrated in rodents, we will pursue these efficacy studies in non-anesthetized large mammal models and will test intravenous as well as intranasal route. Our ultimate goal is to obtain FDA approval for nalfurafine as a treatment of mu-opioid receptor agonist-induced hypoventilation, treatment that could be used in indications ranging from mass casualty to individual victims of opioid intoxication.