# The contribution of the hippocampus to learned opiate tolerance

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $194,293

## Abstract

Project Summary
The utility of opiates for treating pain is limited by the development of tolerance, a phenomenon that can lead to dose-
escalation and an increased liability for dangerous side effects like dependence and overdose. Interestingly,
environmental cues that are paired with opiates can dramatically influence tolerance. Specifically, animals that receive
morphine in a particular context exhibit analgesic tolerance that can be eliminated by simply administering the drug in a
new environment. The cellular and circuit mechanisms underlying this associative form of tolerance have not been well
characterized. However, they are highly relevant clinically as many overdoses occur when addicts take large amounts of
opiates in a new place. In this application, we propose to dissect the circuitry underlying associate morphine tolerance
using modern behavioral neuroscience tools. Specifically, we will combine optogenetic techniques with transgenic
reporter mice to identify the specific neural circuits and cells that mediate associative tolerance. Our central hypothesis
is that context-specific representations in the hippocampus become associated with opiate use and produce a
compensatory response in the amygdala that prevents the inhibition of pain. To test this idea, we will express light
sensitive opsins in the specific neurons that are active during the expression of associative morphine tolerance. We
predict that silencing these cells will prevent tolerance in a morphine-paired context. Stimulating these cells, in contrast,
should induce tolerance in a novel environment that has never been paired with morphine. A similar strategy has been
used to identify and manipulate neurons that encode fear memories in the amygdala, spatial memories in the
hippocampus, cocaine memories in the nucleus accumbens and many others forms of memory. However, to our
knowledge, this approach has never been applied to associative morphine tolerance. We believe that doing so will lead
to significant advances like it has for other forms of learning and memory.

## Key facts

- **NIH application ID:** 10586097
- **Project number:** 5R21DA055440-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Brian J Wiltgen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $194,293
- **Award type:** 5
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10586097

## Citation

> US National Institutes of Health, RePORTER application 10586097, The contribution of the hippocampus to learned opiate tolerance (5R21DA055440-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10586097. Licensed CC0.

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