ABSTRACT
Opioids are the most commonly used and most effective analgesics, and are the first line of defense against
acute and severe pain. However, this dramatic ability to mitigate pain comes with many side effects. These
include constipation, nausea, sedation, dizziness, respiratory depression, dependence, and addiction. Among
these, respiratory depression is the major driver of death by opioid overdose. According to the Center for
Disease Control (CDC), nearly 50,000 people died in 2019 by opioid-induced respiratory depression (OIRD) in
the United States, and the death rate is rising rapidly due to increased misuse and addiction to both
prescription and illicit opioids. Thus, the US is currently experiencing a serious national public health crisis that
is also taking a toll on social economic welfare. Despite these dire numbers, research elucidating the neural
mechanisms of OIRD, which could identify therapeutic targets, has not been rigorously investigated. Animal
studies have shown that OIRD and opioid analgesia are both mediated by the µ-opioid receptor (MOR),
however the neural circuits and brain regions responsible for OIRD and opioid analgesia are not fully
understood. The proposed research aims to dissect the neural circuits that selectively mediate OIRD or opioid
analgesia using cutting-edge molecular, physiological, behavioral, and imaging techniques. Projection-specific
single-cell transcriptomic analysis will then be used to identify functional markers expressed in the MOR-
expressing neurons that specifically mediate OIRD, not opioid analgesia. Successful completion of the
proposed research will identify novel therapeutic targets that selectively rescue OIRD without altering analgesic
effects of opioids.