# Novel mechanisms for correcting opioid-induced synaptic abnormalities

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2022 · $460,780

## Abstract

Abstract
The US is facing a crisis of opioid overdoses and addiction. Current therapies consist largely of alternative
opioids (i.e. maintenance with methadone or buprenorphine) and do not correct neurobiological factors that
underlie drug craving and relapse. These factors include the long-lasting changes at glutamatergic synapses in
the nucleus accumbens (NAc), which both resemble and differ from changes induced by other highly addictive
drugs such as cocaine. Our recent studies suggest these synaptic effects of opioids are opposed by acid-
sensing ion channels (ASICs). ASICs conduct inward Na+ and Ca2+ current at post-synaptic dendritic spines
where they are activated during synaptic transmission by protons released into the synaptic cleft from
neurotransmitter-containing vesicles. Because these protons are removed from the synaptic cleft via the
actions of carbonic anhydrase 4 (CA4), genetically disrupting CA4 or pharmacologically inhibiting CA4 with
acetazolamide (AZD) dramatically increases synaptic ASIC currents. These observations have led to our
hypothesis that AZD will reverse synaptic changes following opioid withdrawal by inhibiting CA4 and
increasing ASIC activity, and thereby reduce craving and relapse. In this proposal we plan to test this
hypothesis by rigorously assessing effects of opioids on synaptic physiology and behavior. Together the
experiments in this proposal will pave the way to a better understanding of the neurobiology underlying opioid
addiction and to new molecular targets for treating opioid use disorder (OUD). Knowledge gained from these
studies could suggest new ways to treat opioid addiction through non-opioidergic mechanisms, for example by
manipulating ASICs, brain pH, or carbonic anhydrase, for which a number of inhibitors are already approved
for human use, and might be efficiently repurposed.

## Key facts

- **NIH application ID:** 10466760
- **Project number:** 5R01DA052953-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** John A Wemmie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $460,780
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466760

## Citation

> US National Institutes of Health, RePORTER application 10466760, Novel mechanisms for correcting opioid-induced synaptic abnormalities (5R01DA052953-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10466760. Licensed CC0.

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