# Investigating a novel regulatory pathway for opioid-induced synaptic plasticity and behavior

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2024 · —

## Abstract

The United States is in the midst of an opioid epidemic and risk is especially high in veterans. Current
therapies consist mainly of alternative opioids, but their efficacy is limited. Thus, new treatments for pain and
addiction are in high demand. Improved knowledge of the mechanisms underlying opioid addiction and relapse
could help predict who might be a risk for addiction, and help to develop better therapies for those already
battling addiction and relapse. The reinforcing effects of opioids depend in large part on the nucleus
accumbens (NAc) and mu opioid receptors, which are expressed at glutamatergic synapses on medium spiny
neurons in the NAc. Opioids and other drugs of abuse can hijack these synapses and alter their number,
morphology, and glutamate receptor subunit composition. These changes are thought to produce abnormal
synaptic states that underlie addiction, withdrawal, craving, and relapse. We recently identified a novel
signaling mechanism that can influence the synaptic and behavioral effects of opiate drugs. This mechanism
involves protons released from presynaptic neurotransmitter-containing vesicles, activation of the post-synaptic
acid sensing ion channel, ASIC1A, and pH buffering at the synapse by carbonic anhydrase 4 (CA4). Our
previous studies and pilot data suggest that ASIC1A plays a critical role in stabilizing glutamatergic synapses
in the NAc, and that loss of ASIC1A increases vulnerability to synaptic abnormalities induced by opioids, as
well as by cocaine. Interestingly, reducing pH buffering by disrupting CA4, increases the inward synaptic Na+
currents mediated by ASIC1A and appears to protect against the synaptic rearrangements thought to
contribute to addiction, craving, and relapse. Here we propose to extensively test the degree to which CA4 and
ASIC1A regulate opioid-induced synaptic abnormalities in the NAc, and influence opioid-reinforced behaviors.
Specific Aim 1 proposes to test the effects of opioids on synaptic physiology in mice lacking ASIC1A, CA4, or
both. Specific Aim 2 proposes to test effects of opioids in these mice in multiple behavioral paradigms
including opioid self-administration, withdrawal, and relapse-related behaviors. We hypothesize that
disrupting ASIC1A will alter synaptic and behavioral effects of opioids, disrupting CA4 will protect against these
effects, and that effects of CA4 disruption will depend on ASIC1A. Together the experiments in this proposal
will pave the way to a better understanding of the neurobiology underlying opioid addiction. Moreover, the
knowledge gained from these studies could suggest new ways to treat opioid addiction through non-opioidergic
pathways, for example by manipulating brain pH, ASICs, or carbonic anhydrase, for which several inhibitors
are already approved for human use.

## Key facts

- **NIH application ID:** 10874372
- **Project number:** 5I01BX004440-05
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** John A Wemmie
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874372

## Citation

> US National Institutes of Health, RePORTER application 10874372, Investigating a novel regulatory pathway for opioid-induced synaptic plasticity and behavior (5I01BX004440-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10874372. Licensed CC0.

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