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

摘要 MU-阿片类激动剂过量与即刻和长期的强直性和节律性收缩有关 吸气肌和呼气肌阻碍呼吸运动达数小时。这种效应被称为阿片类药物 诱发性胸壁僵硬是阿片类药物致低通气性致死性的重要机制。 MU阿片诱导的肌肉“强直”是由蓝斑神经元产生的，可被 Kappa-阿片受体激动剂，但不是目前的呼吸机兴奋剂。我们建议的目标是 在阿片受体激动剂芬太尼过量服用后，证明kappa-阿片受体 激动剂1-恢复被动呼吸力学改变并抑制产生的高代谢 通过芬太尼诱导的肌肉僵硬，2-防止未镇静的大鼠的致命结果。我们将测试呋喃西林， 只有商业上可以买到的kappa激动剂，并表明它抵消了芬太尼的通风效果 服药过量。如果在啮齿动物身上证明了有效性，我们将在非麻醉的大鼠身上继续进行这些有效性研究。 哺乳动物模型，并将测试静脉和鼻腔途径。我们的最终目标是获得FDA的批准 对于作为治疗MU阿片受体激动剂引起的低通气性的纳呋芬，治疗可以是 用于从阿片类药物中毒的大规模伤亡到个别受害者的各种适应症。

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.