Dissecting the mechanisms underlying fentanyl-induced cardiorespiratory depression

Washington University, Saint Louis MO

Investigators

Abstract

PROJECT SUMMARY In the United States, the continued rise in opioid overdose deaths is primarily driven by the synthetic opioid fentanyl, with opioid-induced respiratory depression (OIRD) being the main cause of death. Fentanyl exhibits both a faster onset of OIRD and higher potency for mu opioid receptor (MOR) binding compared to heroin and morphine, making successful intervention strategies more difficult to implement. The increasing availability of the competitive opioid receptor antagonist naloxone, including its widely distributed formulation Narcan, has made it possible for bystanders to readily administer it to someone that has overdosed. However, one major drawback of NLX is that it precipitates immediate withdrawal, which is highly aversive. This presents an additional challenge for someone caring for an individual that has overdosed. While many studies have evaluated central mechanisms underlying OIRD, less attention has been given to peripherally-located MOR. Our preliminary data demonstrate that the peripherally restricted MOR antagonist naloxone methiodide (NLXM) effectively reverses OIRD and is not aversive in rodents. Together, this highlights a substantial peripheral component of OIRD, and suggests that peripheral MOR antagonists may be a viable treatment strategy for managing overdoses without withdrawal or aversion seen with NLX. Many peripherally acting MOR antagonists (PAMORAs) are used for managing opioid induced constipation. Therefore, a primary goal of this grant is to evaluate PAMORAs in the context of fentanyl exposure to determine whether they can be used to prevent or reverse OIRD, and whether reversal of OIRD using these MOR antagonists minimizes withdrawal or aversion in rodents. A secondary goal of this proposal is to evaluate potential peripheral mechanisms underlying OIRD. The nucleus of the solitary tract (nTS) is the first central site that receives sensory afferent information from the periphery. This includes MOR-expressing vagal afferent inputs originating from the nodose ganglion. Our preliminary data demonstrate that fentanyl-induced nTS neuronal activity is mediated by peripheral MOR. Given the presynaptic location of MOR in the nTS, primarily on vagal afferent inputs, a major goal of this proposal is to evaluate a vagal-nTS pathway in the context of OIRD. The nTS is a heterogeneous nucleus containing catecholaminergic, GABAergic and MOR-expressing nTS neurons. These cells receive inputs from vagal afferents, but the role of these subtypes during OIRD is unclear. Overall, these studies aim to 1) repurpose the use PAMORAs to prevent and rescue fentanyl-induced overdoses devoid of unwanted side effects, which may lead to potential new therapeutic avenues; 2) assess the MOR mechanisms in a vagal-nTS pathway mediating OIRD and finally, 3) dissect cell-specific postsynaptic mechanisms within the nTS that contribute to OIRD. Generated studies will help develop novel, life-saving treatment for fentanyl overdoses.