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Unraveling the dynamic mechanisms underlying opioid respiratory depression

Award Number: R01HL144801
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Unraveling the dynamic mechanisms underlying opioid respiratory depression - Project Summary Opioid overdose deaths continue to escalate with a large proportion caused by fentanyl overdoses. To explain why fentanyl is particularly fatal we propose the “triple-hit” hypothesis: Fentanyl targets three distinct but interacting mechanisms that lead to a fatal apnea: (1) Fentanyl causes wooden chest syndrome (WCS) by directly exciting motoneurons due to the inhibition of K+-channels; (2) Fentanyl activates tonic inhibitory neurons that slow rhythmogenesis within the ventral respiratory column (VRC) resulting in the opioid-induced respiratory depression (OIRD). As the network slows, it preserves the rhythmogenic properties of eupneic breathing, but WCS and OIRD together drive the network towards the third hit: (3) Hypoxic conditions. While under normoxic conditions, breathing depends on rotational dynamic interactions among inspiratory and expiratory neurons distributed along the entire VRC; In hypoxia this network reconfigures, becomes silent and dependent on the ballistic activation of inspiratory neurons to generate gasping and autoresuscitation. Although this grant focuses only on these mechanisms, we predict that the three distinct mechanisms will require distinct interventions to slow OIRD, reduce WCS and prevent or reverse the fatal apnea. These three distinct mechanisms are explored in three specific aims: Aim 1 characterizes the fentanyl effects on K+-currents expressed in HEK293 cells to unravel the mechanisms that activate neurons. In synaptically isolated motoneurons we will then characterize the fentanyl effects that lead to the activation of the diaphragmatic EMG. Aim 2 characterizes the opioid-induced transition from OIRD into the fatal apnea: We specifically test the hypothesis that under baseline conditions respiratory rhythmic activity is generated by a distributed network along the VRC. We propose that opioids activate inhibitory neurons in the parabrachial nucleus (PBN) and Kölliker-Fuse (KF) region which in turn inhibit neurons in the VRC and pons. These tonic inhibitory neurons play a significant role in depressing respiratory rhythmogenesis but they preserve the principle rhythmogenic mechanisms of the network. This hypothesis is tested with Neuropixel recordings in urethane-anesthetized, as well as alert freely behaving mice. Viral vectors injected into the medullary and pontine regions will allow us to optogenetically and chemogenetically manipulate inhibitory and excitatory neurons to assess their contributions to OIRD and fatal apnea. Aim 3 will use TRAP2 mice to explore the permanent induction of ASTEp1 Trap2 in neurons that are activated by opioids versus hypoxia. These mice will allow us to histologically characterize as well as optogenetically and chemogenetically manipulate neurons that are differentially activated by opioids versus hypoxia. Aims 1 to 3 complement each other to arrive at a thorough understanding of the network mechanisms that underlie opioid-induced respiratory depression, wooden chest syndrome and the fatal apnea.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $972,132 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	National Center on Sleep Disorders Research	000	5	6/5/2025	COMPETING CONTINUATION	$972,132
														Subtotal = $972,132

Issue Date FY: 2024 ( Subtotal = -$6,759 )
2024	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	National Center on Sleep Disorders Research	000	4	5/13/2024	NON-COMPETING CONTINUATION	-$6,759
														Subtotal = -$6,759

Issue Date FY: 2022 ( Subtotal = $792,048 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	National Center on Sleep Disorders Research	000	4	1/5/2022	NON-COMPETING CONTINUATION	$712,843
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	National Center on Sleep Disorders Research	001	4	6/13/2022	NON-COMPETING CONTINUATION	$79,205
														Subtotal = $792,048

Issue Date FY: 2021 ( Subtotal = $791,342 )
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	National Center on Sleep Disorders Research	002	3	9/16/2021	NON-COMPETING CONTINUATION	$0
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	National Center on Sleep Disorders Research	001	3	5/19/2021	NON-COMPETING CONTINUATION	$79,134
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	National Center on Sleep Disorders Research	000	3	1/4/2021	NON-COMPETING CONTINUATION	$712,208
														Subtotal = $791,342

Issue Date FY: 2020 ( Subtotal = $792,362 )
2020	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Lung Diseases Research	002	2	3/9/2020	NON-COMPETING CONTINUATION	$39,620
2020	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Lung Diseases Research	001	2	1/8/2020	NON-COMPETING CONTINUATION	$752,742
2020	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Lung Diseases Research	000	1	1/7/2020	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $792,362

Issue Date FY: 2019 ( Subtotal = $948,002 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Lung Diseases Research	001	1	8/31/2019	SUPPLEMENT FOR EXPANSION	$139,500
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Lung Diseases Research	000	1	12/31/2018	NEW	$808,502
														Subtotal = $948,002

Grand Total All Awards = $4,289,127

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Unraveling the dynamic mechanisms underlying opioid respiratory depression

Award Number: R01HL144801

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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