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Dissociating respiratory depression and analgesia via a data-driven model of interacting respiratory and pain networks

Award Number: K01DA058543
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Dissociating respiratory depression and analgesia via a data-driven model of interacting respiratory and pain networks - PROJECT SUMMARY This mentored research scientist development award will allow the candidate, Dr. Ryan Phillips, to establish an independent research career focused on understanding the complex circuit interactions that link pain and respiration. The training plan outlined in this award, combined with the candidate's background in brainstem pain circuits and computational modelling, make him ideally suited to successfully follow this career path. Opioid receptors are expressed in multiple brainstem regions that regulate pain and respiration, and the link between opioid-induced analgesia and respiratory depression poses a major clinical challenge. Indeed, the often difficult to predict side-effect of opioid-induced respiratory depression (OIRD) is the leading cause of opioid-related deaths driving the current opioid epidemic. Despite this public health significance, the mechanisms underlying OIRD are not fully understood and therapeutic strategies to prevent or reverse OIRD while maintaining analgesia are limited. A natural idea is that OIRD results from direct effects of opioids on respiratory rhythm-generating neurons of the pre-Bötzinger Complex (preBötC) in the ventral medulla. Although some preBötC neurons do express µ-opioid receptors (µORs), encoded by the Oprm1 gene, systemic opioids continue to produce respiratory depression and apneas even after genetic deletion of µORs in this population. Importantly, the contributions other µORs/Oprm1 expressing respiratory- and pain-related neurocircuitries to OIRD have been described. These brainstem regions, including the parabrachial (PB), Kolliker Fuse (KF), and rostral ventromedial medulla (RVM), all have important roles in regulating the respiratory rhythm generated by the preBötC. However, how opioids alter the network dynamics of these interacting regions remains unknown. We hypothesize that interruption of opioid sensitive network interactions is a major mechanism underlying OIRD caused by systemic opioids. This hypothesis will be tested using computational modeling and experimental approaches performed in tandem. Computational modeling has played a significant role in advancing the field of respiratory neurobiology and is ideally suited for examining the implications of disparate datasets and for low-cost, high throughput testing of hypothesized network features. In addition to existing data, our model will be guided and constrained by new cell-type- and projection- specific experimental manipulations in vivo that will constitute a significant training aspect of this award. By combining these strategies, our data-driven computational model will yield novel insights into the network dynamics that underlie opioid-induced respiratory depression as well as potential therapeutic targets to generate pain relief without respiratory side effects.


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: 2026 ( Subtotal = $100,975 )
2026	2026	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Drug Use and Addiction Research Programs	000	4	3/19/2026	NON-COMPETING CONTINUATION	$100,975
														Subtotal = $100,975

Issue Date FY: 2025 ( Subtotal = $101,477 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Drug Use and Addiction Research Programs	000	3	3/20/2025	NON-COMPETING CONTINUATION	$101,477
														Subtotal = $101,477

Issue Date FY: 2024 ( Subtotal = $94,062 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Drug Use and Addiction Research Programs	000	2	3/13/2024	NON-COMPETING CONTINUATION	$94,062
														Subtotal = $94,062

Issue Date FY: 2023 ( Subtotal = $106,752 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Drug Use and Addiction Research Programs	000	1	3/30/2023	NEW	$106,752
														Subtotal = $106,752

Grand Total All Awards = $403,266

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Dissociating respiratory depression and analgesia via a data-driven model of interacting respiratory and pain networks

Award Number: K01DA058543

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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