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

> **NIH NIH U01** · JOHNS HOPKINS UNIVERSITY · 2024 · $1,136,433

## Abstract

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 an...

## Key facts

- **NIH application ID:** 11140118
- **Project number:** 4U01HL150568-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Michael T Smith
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,136,433
- **Award type:** 4N
- **Project period:** 2019-09-23 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11140118

## Citation

> US National Institutes of Health, RePORTER application 11140118, Effects of experimental sleep disruption and fragmentation on cerebral Mu-opioid receptor function, Mu-opioid receptor agonist analgesia, and abuse liability. (4U01HL150568-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11140118. Licensed CC0.

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