# The influence of astroglial mu opioid receptors in opioid potentiation of HIV neuropathogenesis

> **NIH NIH K99** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $187,151

## Abstract

PROJECT SUMMARY.
Opioid use disorder (OUD) is a critical problem that contributes to the spread of HIV and may intrinsically
worsen neuroHIV pathology. Although the prevalence of antiretroviral therapy (ART) has improved the lifespan
and quality of life of persons infected with HIV (PWH), the viral protein HIV-Tat is still present in the central
nervous system (CNS) of many PWH on ART. Further, almost half of PWH still experience cognitive deficits
and worsened substance misuse outcomes. Opioids can interact with HIV and HIV-Tat to promote
inflammation and exacerbate neuronal damage and dysfunction, leading to increased behavioral and cognitive
deficits, via µ-opioid receptors (MOR) expressed on different cell types. Medium spiny neurons (MSNs) within
the striatum are uniquely vulnerable to the combined effects of opioids and HIV/Tat, and associated with opioid
and HIV/Tat deficits in motivation and reward. The spiraling inflammation between astro- and microglia is
driven by astroglial CCL5-CCL2 inflammatory signaling and is critical to opioid exacerbation of HIV
neuropathology. However, the role of MOR on each cell sub-type are unknown. We hypothesize that the
neuroinflammatory response to combined opioid and HIV/Tat, resulting in increased neuronal damage and
aberrant behavior is largely mediated by MOR activation on astroglia. Aim 1 during the K99 phase will
characterize the impact of astroglial MOR on opioid and HIV-Tat-induced astroglial pathology and dysfunction
in vitro. MOR astroglial-null astroglia will be used to assess neuroinflammation and glutamate buffering, and
MSN survival and morphology. and assessed for opioid reward and in vivo astroglial calcium transients while
freely behaving and awake. Aim 2 (K99) will delineate the loss of MOR activation on astroglia on opioid and
HIV-Tat-induced astroglial pathology and dysfunction in vivo. Tat-tg mice will be crossed with MOR astroglial-
null mice and assessed for reward and in vivo astroglial calcium transients while freely behaving and awake.
Dysfunction will be correlated with neuroinflammation and neuropathology. The above mentored training in
genetically encoded indicators and in vivo calcium imaging combined with advance career development
training will prepare Dr. Nass for the independent R00 phase and be essential in her pursuit of an independent
research program investigating the mechanisms of substance misuse and neurovirology-induced behavioral
dysfunction. Aim 3 (R00) will determine if astroglial activation is required for opioid and HIV-Tat-induced
astroglial destabilization and MSN neuropathology. Tat-tg mice with attenuated astroglial function will be
assessed as described in Aims 1 and 2. The proposed studies will further our understanding of the
mechanisms by which MOR signaling on specific cell sub-type mediates opioid exacerbation of HIV/Tat-
induced inflammation and neuropathology within the reward circuitry and identify possible targets for
therapeutic interventions.

## Key facts

- **NIH application ID:** 10762847
- **Project number:** 1K99DA059324-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Sara Nass
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $187,151
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10762847

## Citation

> US National Institutes of Health, RePORTER application 10762847, The influence of astroglial mu opioid receptors in opioid potentiation of HIV neuropathogenesis (1K99DA059324-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10762847. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*