# Precision pharmacology of the opioids

> **NIH NIH DP1** · HARVARD UNIVERSITY · 2021 · $507,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Substance abuse behaviors result from molecular changes to gene expression programs in neurons over time.
Morphine and heroin are highly addictive opioids that primarily stimulate the mu opioid receptor resulting in short-
term euphoria. The addictive nature of morphine and heroin, unlike natural opioid peptides, may result from their
cell permeability and thus direct influence on gene expression programs leading to addiction. However,
understanding these precise molecular mechanisms is typically challenging due to the dearth of technologies to
precisely map global molecular targets and pathways of a small molecule. We have developed an
interdisciplinary precision pharmacology strategy to map the direct and indirect effects of a small molecule in the
cellular proteome that we propose to apply to these addictive opioids. Our approach draws on the fields of
chemical biology, mass spectrometry and data science to enable insight to the full range of molecular
interactions, the structural biology underlying the interaction site, and changes to downstream pathways in a
single experiment. The strategy involves: (1) treatment of whole cells with the small molecule of interest, (2)
isolation of the resulting global molecular binding sites and (3) confident mass spectrometry-based assignment.
We recently applied this platform to study three non-steroidal anti-inflammatory drugs (NSAIDs). Our results
revealed several protein complexes involved in gene expression that the NSAIDs interact with, including a
directly with the nucleosome. These results point to the vast web of molecular mechanisms that is now
observable by precision pharmacology. In this proposal, we will apply our technology to morphine and heroin to
determine their direct influence on gene expression leading to substance abuse. We will first develop a set of
“click opioids” and “photo-click opioids” as generally useful probes for tracking opioid mechanisms in biology.
We will specifically apply these probes to characterize opioid-driven genetic and epigenetic regulation in neuronal
cells first in tissue culture and subsequently to mouse models of addiction. With a global map of the opioid
interactome, these data will reveal direct opioid interactions with nucleosomes by binding, covalent modification,
or mediating acetylation marks, and the indirect influence on upstream transcriptional programs that drive gene
expression changes. By characterizing the broader interactions of the opioids, we are poised to expose
molecular mechanisms leading to addiction, identify novel targets for new therapeutics and diagnostics, and
open new paradigms in biological regulation by small molecules. The outlined research is a conceptually novel
approach to perform mechanism of action studies that is suitable for the Avenir Award due to the broad potential
for impact and early stage of this research.

## Key facts

- **NIH application ID:** 10242770
- **Project number:** 5DP1DA046586-04
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Christina Woo
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $507,000
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242770

## Citation

> US National Institutes of Health, RePORTER application 10242770, Precision pharmacology of the opioids (5DP1DA046586-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242770. Licensed CC0.

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