# Exploring the Role of Alternatively Spliced Variants of the Mu Opioid Receptor Gene, Oprm1, in Opioid-Induced Respiratory Depression in Gene Targeted Rat Models

> **NIH NIH F31** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $44,426

## Abstract

PROJECT SUMMARY/ABSTRACT
Opioids derived from opium are amid the oldest medications dating back to the 1800s, originally used for
gastrointestinal distress and now are among the most effective treatments for pain management. It wasn’t until
the mid-1800s that the abuse potential for opioids was evident, and this problem has since multiplied on an
international scale. Within the last decade, the number of opioid overdose deaths per year in the United States
alone has more than tripled. It is therefore urgent to not only find solutions to combat opioid overdoses, but to
also develop new treatments for pain management. Opioid-induced respiratory depression (OIRD), the main
cause of opioid overdose deaths, is primarily mediated through mu opioid receptors, particularly in two small
brainstem regions, the preBötzinger complex (preBötC) and the parabrachial complex (PBN) that are sufficient
and necessary to drive OIRD. Recent reports have also highlighted important cell types and downstream
molecular mechanisms within these brain regions that mediate OIRD. Moreover, several laboratories within the
last few decades have been exploring the function of the mu opioid receptor gene, Oprm1, which undergoes
extensive alternative splicing to generate two classes of splice variants: Exon 1- (E1) and Exon 11- (E11)
associated variants. The functional relevance of these splice variants has been demonstrated in mediating the
actions of various mu opioids, including analgesia, tolerance, physical dependence and reward. However, it
remains unknown how the two sets of Oprm1 splice variants influence OIRD. Preliminary data and unpublished
data from our laboratory demonstrate differential actions of E1- and E11-associated variants in OIRD from
varying doses of fentanyl and morphine in our rat models. Therefore, the overarching hypothesis is that the two
classes of Oprm1 alternatively spliced variants (i.e., E1- and E11-associated variants) in the preBötC and PBN
differentially influence OIRD. Aim 1 examines the role of E1- and E11-associated variants within two key brain
regions modulating respiration, preBötC and PBN, on OIRD in rats, and will be completed in Year 1 of this
fellowship training. Aim 2 identifies the expression of E1- and E11-associated Oprm1 variants within various
cell types of the preBötC & PBN in rats (Year 2). To test these aims, we generated two gene targeted rat
models, in which Oprm1 E1- or E11-associated splice variants can be conditionally deleted. Comprehension of
the distinct roles of E1- and E11-dependent variants on OIRD in these two brain regions and in key cell types
within these regions is expected at the end of this proposed project. Investigation of how these effects are
altered by different opioids, doses, and sexes will also be assessed. The proposed study will advance our
understanding of Oprm1 alternative splicing mechanisms and their role in OIRD, allowing us to develop
therapeutic strategies to combat OIRD.

## Key facts

- **NIH application ID:** 10997607
- **Project number:** 1F31DA060029-01A1
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Ayma Malik
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,426
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997607

## Citation

> US National Institutes of Health, RePORTER application 10997607, Exploring the Role of Alternatively Spliced Variants of the Mu Opioid Receptor Gene, Oprm1, in Opioid-Induced Respiratory Depression in Gene Targeted Rat Models (1F31DA060029-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10997607. Licensed CC0.

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