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Preserving Respiratory Motor Function and Plasticity with Opioid Receptor Acting Agonists

Award Number: R21DA065417
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Preserving Respiratory Motor Function and Plasticity with Opioid Receptor Acting Agonists - Project Summary and Abstract Widely regarded as the gold-standard for analgesic drugs, mu opioid receptor (MOR) acting agents, including morphine, fentanyl, and carfentanil, also provide a high risk for respiratory depression and death. Towards allowing for its effective and robust analgesic effects while minimizing potential fatalities, many studies have investigated the impact of MOR activation on central nervous system respiratory motor circuitry. Ideally, the holy grail of analgesic drugs would be synthesis of a MOR acting agent with effective pain relief without respiratory depression. Excitingly, we recently discovered a potent opioid agonist, we termed atoxifent, which displayed minimal respiratory depression. Indeed, administration of atoxifent led to long-lasting anti- nociception with minimal respiratory depression as measured through whole body plethysmography (WBP). With this initial discovery, more studies are necessary in order to characterize this potentially breakthrough therapy and its applicability in the human clinical setting. Towards this goal, critical gaps in knowledge include investigating: 1) the capacity of atoxifent treated animals to respond to respiratory challenge including hypoxia and hypercapnia and 2) the potential to display respiratory plasticity. Preliminary data suggests that relative to fentanyl, there is a robust ventilatory response of atoxifent administered rats when exposed to a hypoxia challenge. Based on these initial observations, it is our overall hypothesis that atoxifent will preserve the ability to respond appropriately to respiratory challenge, as well as manifest ventilatory plasticity in both intact and in conditions where there may already be compromised breathing effort. We propose the following Specific Aims: Specific Aim 1: Test the hypothesis that administration of the MOR agonist, atoxifent, will not only prevent opioid induced respiratory depression but will preserve the capacity to respond to a hypoxic-hypercapnic challenge and display respiratory plasticity. Specific Aim 2: Test the hypothesis that treatment with atoxifent will preserve the ability to respond to hypoxia-hypercapnia, as well as maintain the ability to manifest respiratory plasticity in breathing compromised animals. These straightforward studies will help to elucidate the potential of a breakthrough MOR acting drug with potent analgesic activity with minimal respiratory depression. If indeed it is shown that both intact and respiratory compromised animals preserve not only baseline respiratory motor activity but can also respond to respiratory challenge and manifest respiratory plasticity, this will help build an argument towards moving forward towards a safe MOR analgesic agent.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $231,000 )
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Drug Use and Addiction Research Programs	000	1	9/8/2026	NEW	$231,000
														Subtotal = $231,000

Grand Total All Awards = $231,000

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Preserving Respiratory Motor Function and Plasticity with Opioid Receptor Acting Agonists

Award Number: R21DA065417

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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