# Role of astrocytes and astrocytic CD38 in spinal opioid signaling

> **NIH NIH R36** · UNIVERSITY OF MINNESOTA · 2022 · $53,240

## Abstract

Project Summary
Opioids are commonly prescribed for the treatment of pain, and the classic mechanism of opioid signaling
involves neuronal mechanisms. Chronic opioid administration results in negative effects like paradoxical
hyperalgesia and opioid tolerance and can lead to dependence and addiction. These negative effects are not
explained by neuronal mechanisms alone. Understanding the role of non-neuronal cells in opioid signaling
during normal and pathological conditions is important for the development of novel pain interventions.
Astrocytes, classically considered supportive cells, are now known to have important roles in modulating
synaptic transmission and extrasynaptic glutamate a key neurotransmitter in pain and opioid analgesia. In the
nucleus accumbens, an important brain region for addiction pathways, astrocytes have been shown to express
µ-opioid receptors (MOR) and to respond to opioids with calcium elevations and glutamate release. Despite
their critical role in modulating synaptic transmission and extrasynaptic glutamate, no studies have determined
whether astrocytes play a role in µ-opioid signaling in the spinal cord, an important region for pain processing
and opioid antinociception. Our preliminary behavioral experiments show that the protein CD38, an important
protein responsible for calcium homeostasis, is expressed exclusively in astrocytes in the spinal cord, and
animals deficient in CD38 had markedly reduced antinociceptive efficacy to morphine administered
intrathecally, pointing to a role of astrocytic CD38 in spinal opioid mechanisms. Therefore, our current
objectives are to define at the synaptic level: i) the role of spinal astrocytes in µ-opioid signaling and ii) the role
of spinal astrocytic protein CD38, in µ-opioid signaling and antinociception. We hypothesize that astrocytes are
involved in spinal opioid signaling via mechanisms that engage the astrocytic calcium protein CD38 and its
metabolite cADPR. To test this hypothesis, we will perform ex vivo calcium imaging of spinal cord astrocytes
using newly developed genetically encoded calcium indicators and electrophysiological readouts to measure
the release of glutamate by astrocytes following opioid stimulation. To test the role of astrocytic CD38 in
antinociception at the synaptic level, we will measure the ability of the opioid to inhibit optogenetic neuronal
synaptic stimulation of Nav 1.8 nociceptors. Comparisons will be made between our wild type and CD38
deficient mice. Our results will characterize the involvement of astrocytes and astrocytic CD38 in µ-opioid
signaling at the spinal level and would define the promising underexplored potential of astrocytes as novel
targets for the development of pain interventions with reduced addiction liability.

## Key facts

- **NIH application ID:** 10452235
- **Project number:** 1R36DA054455-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Ruth E Quintana
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $53,240
- **Award type:** 1
- **Project period:** 2022-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452235

## Citation

> US National Institutes of Health, RePORTER application 10452235, Role of astrocytes and astrocytic CD38 in spinal opioid signaling (1R36DA054455-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10452235. Licensed CC0.

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