#  opioid receptor activation of the carotid body mitigates OIRD by fentanyl

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $712,167

## Abstract

ABSTRACT
Fentanyl is a widely used opioid in the clinic for relieving chronic pain. Fentanyl abuse leads to mortality due to
opioid-induced respiratory depression (OIRD). OIRD is a major health concern in the USA and there is an
unmet need for developing therapeutic strategies for mitigating OIRD. Breathing is regulated by brainstem
neurons generating respiratory rhythm. Sensory feedback from carotid body (CB) chemoreceptors, which
stimulate breathing, is an important regulator of breathing. Current evidence suggests that OIRD is in part due
to fentanyl-induced inhibition of brainstem neurons by µ-opioid receptors (MORs). the effects of fentanyl on CB
are not known. Preliminary data showed fentanyl stimulates CB sensory nerve (CSN) activity acting on κ-
opioid receptors (κ-ORs) and co-administration of fentanyl and a κ-OR agonist prevent OIRD. Based on these
observations, we will test the hypotheses: a) fentanyl stimulates CB acting as a partial κ-OR agonist by
elevating [Ca2+]I in glomus cells through κ-OR-Gαq signaling and b) full activation of CB with co-application of
fentanyl and a κ agonist mitigate OIRD without compromising analgesic effects of fentanyl. These hypotheses
are tested in rats and mice using repertoire of approaches. Studies in AIM 1 determine relative abundance of
κ-ORs in the rat and murine CBs and assess their role in CB activation by fentanyl. AIM 2 delineate the role of
κ-OR-Gαq signaling in [Ca2+]I elevation by fentanyl in glomus cells and assess its significance in CB activation.
AIM 3 tests the hypothesis that co-application of fentanyl and κ-OR agonist mitigate OIRD without
compromising analgesic efficacy of fentanyl and assess whether CB is the site of action. Major conceptual and
technical innovations include that a) Fentanyl activates CB through κ-ORs as opposed to inhibition of
brainstem neurons by µOR; b) Mitigating OIRD with κ-OR agonist is a hitherto unexplored concept that may
have important therapeutic implications and c) Integrating various standard and state-of-the-art approaches
provide information at the systems level and cellular insights. The proposed studies provide much-needed
framework for developing novel therapeutic strategies for mitigating OIRD.

## Key facts

- **NIH application ID:** 10928988
- **Project number:** 1R01HL174373-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Nanduri R Prabhakar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $712,167
- **Award type:** 1
- **Project period:** 2024-09-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10928988

## Citation

> US National Institutes of Health, RePORTER application 10928988,  opioid receptor activation of the carotid body mitigates OIRD by fentanyl (1R01HL174373-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10928988. Licensed CC0.

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