# Physiological and Molecular Mechanisms of Mu Opioid Receptors in Motivation and Affect

> **NIH NIH R00** · WASHINGTON UNIVERSITY · 2024 · $248,999

## Abstract

Project Summary:
The primary goal of this training proposal is to understand, with mechanistic granularity, how mu opioid receptors
(MORs) modulate motivated `wanting' versus affective `liking' in nucleus accumbens (NAc). During the proposed
K99 training period, I will be trained in two in vivo physiology/imaging approaches (fiber photometry and 1-photon
microscopy) and on intracellular/molecular effector systems. Additionally, I will actively participate in
professional/career training opportunities and have frequent meetings with my mentoring committee to prepare
to apply and succeed in an independent faculty position. The first research aim of my proposal seeks to
understand the temporal dynamics and effects of endogenous MOR signaling in the DRNEnkNAc pathway. My
previous postdoctoral research, using pharmacology, genetics, and optogenetics/chemogenetics, has identified
the terminals of an enkephalinergic dorsal raphe nucleus projection to NAc as the site of MOR action for
modulating food intake behaviors. To better understand how MOR signaling affects this pathway, I will use two
in vivo imaging approaches, fiber photometry and microendoscopy, to determine how endogenous MOR signals
shape neural circuit activity during motivated behaviors (Aim 1, K99). Additionally, because the roles of specific
intracellular signaling cascades have not been well defined in brain reward circuits, I will manipulate G-protein
and beta-arrestin signaling pathways to determine how each of them contributes to behavior (Aim 2, K99). During
the K99 phase, I will also be preparing to lead my own research lab. I will actively participate in scientific society
leadership positions (chairing symposia, steering committees), learn about how to direct a lab (budgeting and
administrative tasks), and continue to further my scholarly knowledgebase (planned interactions with my mentor
and committee members). For the R00 “independent” phase of my proposal, I propose to build on the mentored
training above to examine what mechanisms and circuits underlie MOR-mediated affective `liking' in NAc (Aim
3). These studies are of interest because growing evidence suggests that though NAc MORs can robustly
modulate both motivation and affect, they likely do so via different neural mechanisms. Understanding how these
biopsychological systems are dissociable, even within a specific neurochemical class, has important implications
for developing novel therapeutic drugs that are efficacious without also having a propensity for abuse. I will
selectively disrupt or restore MOR function using multiple genetic mouse models and viral vector interventions,
as well as record endogenous neuronal responses in vivo using microendoscopic approaches. I will perform
these experiments while testing mice on the affective test reactivity (TR) test, which classifies and quantifies
innate orofacial reactions to taste stimuli and has been used effectively for decades to measure the affective
value of taste st...

## Key facts

- **NIH application ID:** 10775813
- **Project number:** 5R00DA049862-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Daniel Charles Castro
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $248,999
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10775813

## Citation

> US National Institutes of Health, RePORTER application 10775813, Physiological and Molecular Mechanisms of Mu Opioid Receptors in Motivation and Affect (5R00DA049862-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10775813. Licensed CC0.

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