# Alternative pre-mRNA splicing of mu opioid receptor gene and mu opioid actions

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2021 · $365,003

## Abstract

Project Summary/Abstract
Mu opioid receptors play a fundamental role in mediating the actions of morphine and most clinical analgesics,
as well as drugs of abuse, such as heroin. The single-copy mu opioid receptor gene (OPRM1) creates an array
of splicing variants by undergoing extensive alternative pre-mRNA splicing (AS), that is conserved from
rodents to humans. These splice variants are categorized into three types based on receptor structure: 1) Full-
length carboxyl (C-) terminal variants with 7-transmembrane (TM) domains; 2) Truncated variants containing 6-
TM domains; and 3) Truncated variants containing single TM. Increasing evidence suggests that the OPRM1
AS variants are pharmacologically important. Several C-terminal variants display marked differences in region-
specific expression, mu agonist-induced G protein coupling, phosphorylation, internalization and post-
endocytic sorting. MOR-1D is responsible for morphine-induced itch. Dysregulation of several variant mRNA
expressions has been observed in a number of cell and animal models, as well as human diseases. Evidence
from our three knockout mouse models suggest that individual C-terminal sequences generated through
alternative 3' splicing play distinct roles in various morphine actions, including tolerance, physical dependence
and reward. Additionally, intracerebroventricular (i.c.v.) administration of an antisense vivo-morpholino
antisense oligo, which blocks 3' splicing from exon 3 to exon 7, significantly attenuates morphine tolerance in
mice. Together, these studies not only strongly support our hypothesis that OPRM1 alternative splicing
contributes to the regulation of complex opioid actions in animals and humans, but also provide a compelling
rationale and scientific premise for further study of the molecular mechanisms controlling OPRM1 alternative
splicing and assessing the impact of modulating OPRM1 alternative splicing using antisense vivo-morpholino
oligos on morphine actions, as proposed in this application. The primary goal of this application is to further
investigate mechanisms and functions of OPRM1 gene alternative splicing by using a variety of in vitro and in
vivo approaches. The specific aims include: 1) Decoding molecular mechanisms underlying OPRM1 3' splicing
by identifying cis-acting elements and trans-acting factors that regulate the 3' splicing; 2) Investigating the role
of the OPRM1 3' splicing in mu opioid actions in both Be(2)C cells and mice using an antisense vivo-
morpholino oligo approach. The proposed studies promise to generate significant insights into the mechanism
and function of OPRM1 3' splicing, and may have the potential for developing new therapeutics for controlling
pain and alleviating the detrimental side-effects of mu opioids.

## Key facts

- **NIH application ID:** 10166814
- **Project number:** 5R01DA042888-06
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** YING-XIAN PAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $365,003
- **Award type:** 5
- **Project period:** 2020-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166814

## Citation

> US National Institutes of Health, RePORTER application 10166814, Alternative pre-mRNA splicing of mu opioid receptor gene and mu opioid actions (5R01DA042888-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10166814. Licensed CC0.

---

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