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Opioid Modulation of Retinal Ganglion Cells Providing Photoentrainment of the Circadian Clock

Award Number: R01EY029227
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Opioid Modulation of Retinal Ganglion Cells Providing Photoentrainment of the Circadian Clock - Abstract Opiates are the cornerstone of analgesic therapy, but also produce numerous side effects. Besides their high propensity for addiction, repeated opioid administration leads to progressive sleep disorders, expressed as worsening insomnia and daytime sleepiness/sleeping. Opioid- induced sleep disorders (OISDs) are strong predictors of multi-substance use disorders, and psychiatric comorbidities including suicidal ideation. The primary target of opioid analgesic drugs is the µ-opioid receptor (MOR). MORs are widely expressed within the sleep/wake circuitry, therefore systemically delivered opioids might interfere with sleep at multiple sites of action. Importantly, no consensus has been reached on which specific CNS sites therapeutic or abused opioids act upon to trigger OISD, nor do current therapies specifically address OISD. Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) synchronize the sleep/wake schedule to environmental cycles of light/darkness (“photoentrainment”) by sending light-evoked spike trains to the brain in humans and most mammals. Our recent work demonstrated that ipRGCs express MORs by which MOR-selective agonists directly inhibit the light responses of ipRGCs. Furthermore, we have shown that upon chronic, systemic delivery, morphine accumulates in the eye, and acts on MORs expressed by ipRGCs to alter the regular rhythm of sleep/wake while contributing to the chronic morphine-triggered behavioral sensitization. The objectives of the current proposal are to analyze whether kinetics of opioid deposition in the eye along with specifics of MOR signaling in ipRGCs directly contribute to the gradually worsening OISD. We will also test if antagonist of MORs delivered in engineered nanoparticles into the eye can reduce OISDs. The results will provide a mechanistic description of a novel neural pathway by which systemically administered opioids alter sleep/wake cycle. Additionally, the results will show the feasibility of using intravitreal MOR selective antagonists to reduce the severity and inherent comorbidities of sleep disorders in patients receiving long-term opioid therapies.


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 = $373,987 )
2025	2025	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Vision Research	000	6	7/3/2025	NON-COMPETING CONTINUATION	$373,987
														Subtotal = $373,987

Issue Date FY: 2024 ( Subtotal = $373,766 )
2024	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Vision Research	001	5	7/5/2024	NON-COMPETING CONTINUATION	$373,766
2024	2021	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Vision Research	000	3	6/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $373,766

Issue Date FY: 2023 ( Subtotal = $386,458 )
2023	2023	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Vision Research	000	4	9/15/2023	COMPETING CONTINUATION	$386,458
														Subtotal = $386,458

Issue Date FY: 2021 ( Subtotal = $362,590 )
2021	2021	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Vision Research	000	3	6/23/2021	NON-COMPETING CONTINUATION	$362,590
														Subtotal = $362,590

Issue Date FY: 2020 ( Subtotal = $374,264 )
2020	2020	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Vision Research	000	2	6/22/2020	NON-COMPETING CONTINUATION	$374,264
														Subtotal = $374,264

Issue Date FY: 2019 ( Subtotal = $374,689 )
2019	2019	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Vision Research	000	1	9/16/2019	NEW	$374,689
														Subtotal = $374,689

Grand Total All Awards = $2,245,754

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Opioid Modulation of Retinal Ganglion Cells Providing Photoentrainment of the Circadian Clock

Award Number: R01EY029227

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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