# The Nociceptin ORL1 System: Treatment Target for Relapse

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $346,968

## Abstract

Treatment with naltrexone (NTX), a nonselective µ, d, k (MOP, DOP, KOP) classical opioid receptor antagonist,
is considered a gold standard of care for alcohol use disorder (AUD). Nonetheless, there is an urgent need for
novel and more efficacious pharmacological approaches to AUD since only a minority of patients benefit from
NTX. Findings of the previous funding periods suggest that both innate and chronic EtOH-induced
overexpression of classical opioid receptors contribute to enhanced motivation for EtOH whereas activation of
the antiopioid nociceptin/orphanin (N/OFQ) receptor (NOP) system reduces EtOH intake and seeking.
Preliminary data supporting this renewal suggest that simultaneous blockade of classical opioid receptors with
concurrent activation of NOP has superior efficacy compared to classical opioid receptor antagonists such as
NTX or manipulation of single receptor subtypes. These findings provide a solid foundation for a systematic
investigation of the therapeutic potential of a novel pharmacological agent (BU10119) that blocks MOP, DOP,
and KOP receptors while activating NOP receptors. The major objective of this project, therefore, is to establish
the efficacy of BU10119 (and, by inference, mixed nonselective classical opioid antagonists/NOP agonists) for
AUD treatment as well as the neurobiological basis of BU10119’s actions. Specific Aim 1 will establish the
effects of acute BU10119 vs. NTX on EtOH drinking and context or stress-induced EtOH seeking in rats with
intact NOP function [nondependent Wistar rats (ndW)] compared to both rats with innate [Marchigian Sardinian
alcohol preferring rats (msP)] and chronic EtOH-induced [(postdependent Wistar rats (pdW)] NOP
overexpression and rats with deficient NOP function [NOP-knockout (NOP-KO) rats]. Specific Aim 2 is designed
to characterize the effects of BU10119 in the context of chronic treatment. This objective is translationally
relevant as well as necessary given the known sensitivity of N/OFQ-NOP function to adaptive changes with
repeated pharmacological manipulation and will establish the direction in which such possible changes modify
the effects of BU10119 vs. NTX. Specific Aim 3 will elucidate how recruitment of the N/OFQ system contributes
to the efficacy BU10119 by establishing the effects of concurrent classical opioid receptor blockade and NOP
activation and by identifying the brain site(s) in which NOP activation conveys enhanced efficacy to mixed MOP,
DOP, KOP antagonists / NOP agonists. Successful completion of this project is expected (a) to define the
therapeutic potential of drugs acting as classical opioid receptor antagonists / NOP agonists for AUD treatment
while directly informing the development of BU10119 as an AUD therapeutic, and (b) to generate novel
information on the neural basis of the “anti-addiction” effects of this class of pharmacological agents.

## Key facts

- **NIH application ID:** 10847466
- **Project number:** 5R01AA014351-18
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Friedbert Weiss
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $346,968
- **Award type:** 5
- **Project period:** 2004-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10847466

## Citation

> US National Institutes of Health, RePORTER application 10847466, The Nociceptin ORL1 System: Treatment Target for Relapse (5R01AA014351-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10847466. Licensed CC0.

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