# Howard University Research Center for Minority Health and Health Disparities

> **NIH NIH U54** · HOWARD UNIVERSITY · 2022 · $77,250

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Ozra Dehkordi, Ph.D
ABSTRACT
The most frequent cause of death associated with opioid overdose is respiratory depression. The respiratory
depressant effects of opioids are mainly mediated by G-protein-gated inward rectifying potassium channels
subunit 2 (GIRK2) expressed by the respiratory rhythm generating neurons of the pre-Bötzinger complex.
GIRK2 are also known to be implicated in opioid-induced analgesia. However, biochemical and metabolic
changes associated with opioid activation of GIRK2 in the pre-Bötzinger and brainstem pain sensitive sites such
as rostral ventral medulla (RVM), is still unknown. In the present study in mice, we hypothesize that 1) the
metabolomic changes in the RVM and pre-Bötzinger complex associated with long-term subcutaneous
morphine administration, is due to activation of GIRK2 channels expressed by pain sensitive cells of the
RVM and neurokinin-1 receptor (NK-1R) expressing rhythm generating cells of the pre-Bötzinger
complex; and that 2) this activation leads to an imbalance between excitatory and inhibitory
neurotransmitters and their metabolites in the immediate vicinity of pre-Bötzinger complex and RVM.
We will test this hypothesis using in vivo proton magnetic resonance spectroscopy (1H MRS) in wild-type and
GIRK2 heterozygous (GIRK2+/-) mutant mice. We will analyze changes in the concentration of glutamate,
glutamine, GABA, glycine and other metabolites in the pre-Bötzinger complex and RVM before and 6-7 days
after subcutaneous implantation of morphine (75 mg pellets) and/ or placebo pellets (control). The results will
provide valuable information regarding cellular and biochemical changes associated with morphine activation
of GIRK2 at the pre-Bötzinger and RVM. The results also has the potential to enable the study of brain
metabolites involved in opioid-induced analgesia at the RVM and opioid-induced respiratory depression at the
pre- Bötzinger complex.
OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

## Key facts

- **NIH application ID:** 10559951
- **Project number:** 3U54MD007597-34S1
- **Recipient organization:** HOWARD UNIVERSITY
- **Principal Investigator:** William M. Southerland
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $77,250
- **Award type:** 3
- **Project period:** 1997-09-30 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10559951

## Citation

> US National Institutes of Health, RePORTER application 10559951, Howard University Research Center for Minority Health and Health Disparities (3U54MD007597-34S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10559951. Licensed CC0.

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