Saturday, November 23, 2024 11/23/2024

Effects of experimental sleep disruption and fragmentation on cerebral Mu-opioid receptor function, Mu-opioid receptor agonist analgesia, and abuse liability.

Award Number: U01HL150568
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Chronic pain and opioid use disorders (OUD) are burgeoning interrelated epidemics. There is a major public health need to investigate modifiable risk factors and elucidate the pathophysiology of these poorly understood disorders so that novel therapies and prevention efforts can be developed. Sleep disturbances, especially insomnia and sleep apnea are highly prevalent, treatable and increasingly recognized as risk factors for both chronic pain and OUD. It is not known, however, whether sleep disturbance causally alters mechanisms that contribute to OUD risk. Sleep disruption impairs endogenous pain inhibition; a phenomenon associated with descending neural pathways that are linked to both the analgesic efficacy and rewarding properties mu-opioid receptor (MOR) agonists. This suggests that cerebral MOR dysregulation may be a shared neurobiological mechanism by which sleep disturbance causally increases risk for chronic pain and OUD. Direct interrogation of cerebral MOR availability, however, has yet to be undertaken after experimental sleep deprivation in humans. Based on preclinical data and our preliminary studies, we hypothesize that sleep continuity disruption (SCD) and/or sleep fragmentation (SF), two sleep patterns commonly observed in both chronic pain and OUD, will alter cerebral MOR availability in descending pain inhibitory and reward processing pathways. We further hypothesize that these forms of sleep disruption will increase OUD risk by reducing opioid analgesic efficacy and/or enhancing standard abuse liability measures. We propose a parallel group experiment that will randomize 100 healthy subjects to two nights of either experimental: 1) SCD (frank, prolonged, nightly awakenings with curtailed sleep duration, a pattern associated with insomnia); 2) SF (multiple, frequent, non- waking arousals with preserved sleep duration, a pattern observed in sleep apnea); or 3) undisturbed sleep (US). Subjects will then complete two [11C]Carfentanil PET brain imaging scans (resting to measure basal MOR binding potential (BP) and during pain to quantify endogenous opioid release). We will then use a placebo- controlled, cumulative dose paradigm to evaluate the analgesic efficacy and abuse liability of the prototypic MOR agonist, hydromorphone. Analgesic efficacy and abuse liability will be evaluated using quantitative sensory testing and standard procedures. We aim to: 1) evaluate whether experimental SCD and/or SF alter resting or pain-evoked MOR BP in brain regions associated with pain inhibition; 2) examine whether SCD and/or SF alters the analgesic response and abuse liability profile of hydromorphone; and 3) determine whether MOR BPs in brain regions of interest are associated with hydromorphone analgesia and abuse liability. We will also evaluate the extent to which associations differ by sleep condition or sex. Establishing whether common and treatable forms of sleep disturbance directly alter cerebral MOR availability, opioid analgesia and abuse liability will transform the understanding of how sleep disturbance is a risk factor for OUD and chronic pain and lead to novel prevention efforts and changes in pain management practice.


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 = -$628,300 )
2025	2021	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	000	1	10/1/2024	SUPPLEMENT FOR EXPANSION	-$628,300
														Subtotal = -$628,300

Issue Date FY: 2024 ( Subtotal = $1,136,433 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	000	2	9/3/2024	EXTENSION WITH OR WITHOUT FUNDS	$1,136,433
														Subtotal = $1,136,433

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	000	1	8/18/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $581,018 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	000	1	1/8/2021	SUPPLEMENT FOR EXPANSION	$581,018
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	002	1	3/2/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	001	1	2/25/2021	NEW	$0
														Subtotal = $581,018

Issue Date FY: 2019 ( Subtotal = $4,717,518 )
2019	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	000	1	9/21/2019	NEW	$4,717,518
														Subtotal = $4,717,518

Grand Total All Awards = $5,806,669

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Effects of experimental sleep disruption and fragmentation on cerebral Mu-opioid receptor function, Mu-opioid receptor agonist analgesia, and abuse liability.

Award Number: U01HL150568

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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