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

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2023 · $386,458

## Abstract

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.

## Key facts

- **NIH application ID:** 10736610
- **Project number:** 2R01EY029227-04
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Jozsef Vigh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $386,458
- **Award type:** 2
- **Project period:** 2019-09-30 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10736610

## Citation

> US National Institutes of Health, RePORTER application 10736610, Opioid Modulation of Retinal Ganglion Cells Providing Photoentrainment of the Circadian Clock (2R01EY029227-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10736610. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*