Abstract
The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose- opioid-induced respiratory depression. Here, we identify two primary changes to murine breathing after administering opioids. These changes implicate the brainstem's breathing circuitry which we confirm by locally eliminating the µ-Opioid receptor. We find the critical brain site is the preBötzinger Complex, where the breathing rhythm originates, and use genetic tools to reveal that just 70-140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.
Highlights
400,000 people in the United States died from a drug overdose involving a prescription or illicit opioid between 1999 and 2017 [1]
We show that two small brainstem sites are sufficient to rescue opioid induced respiratory depression
Characterization of these neurons and their molecular response to opioids may reveal a strategy for separating respiratory depression from analgesia and enable the development of novel opioids or related compounds that relieve pain without risk of overdose
Summary
400,000 people in the United States died from a drug overdose involving a prescription or illicit opioid between 1999 and 2017 [1]. This epidemic is not unique to the United States and with the increasing distribution of highly potent synthetic opioids like fentanyl, it has become a global public health emergency [2]. In both the central and peripheral nervous systems, including sites that could modulate breathing such as: the cerebral cortex, brainstem respiratory control centers, primary motor neurons, solitary nucleus, and oxygen sensing afferents [5,6]. Either one or multiple sites could be mediating the depressive effects of opioids on breathing
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