Stewart Clark, PhD, is using a National Institute on Drug Abuse grant to seek proof of concept that Neuropeptide S receptor-targeted molecules can mitigate opioid seeking.
Seeking Therapeutic Target for Opioid Use Treatment
By Dirk Hoffman
Published February 19, 2025
A Jacobs School of Medicine and Biomedical Sciences researcher has received National Institutes of Health funding to gain better understanding of the neural mechanisms underpinning drug-mediated reward, persistent drug-taking and relapse behavior.
Stewart Clark, PhD, associate professor of pharmacology and toxicology, is principal investigator on a two-year, $420,000 grant titled “Preclinical Trial: Targeting the Neuropeptide S Receptor to Curb Opioid Taking and Seeking” from the National Institute on Drug Abuse.
Studying NPS Receptor as Possible Therapeutic Target
Clark notes that substance use disorders have a devastating impact on individuals, families, and society and that present pharmacological treatments do not fully ameliorate patients’ symptoms and in many cases are unable to treat the full spectrum of symptoms.
“Therefore, it is paramount to identify new targets for pharmacological intervention,” he says.
The Neuropeptide S (NPS) receptor, when activated in rats, facilitates reward-related behaviors (e.g., cocaine seeking). Paradoxically, NPS receptor activation is also anxiolytic-like, Clark says.
As part of the researchers’ drug discovery efforts, a paper published in the journal Neuropharmacology in December 2023 reported the discovery of a NPS receptor-targeted molecule that retains the anxiolytic-like properties, but reduces cocaine-seeking behaviors.
Regarding opioids, the levels of NPS receptor changes in rats that have been made dependent on morphine, and levels of the receptor further change after withdrawal. Therefore, the data suggest that the NPS system may be a prime target for addressing the unmet therapeutic need of substance use disorders, Clark says.
“Neuropeptide S receptor ligands are known to reduce cocaine seeking and taking in rats. We will test these same ligands for effects against opioid seeking (oxycodone),” he notes.
Preclinical Models of Substance Use Disorder
The researchers will incorporate various protocols that allow rats to intravenously self-administer oxycodone.
To understand the mechanism by which NPS receptor-targeted molecules produce their effects, the fundamental circuit pathway and behavioral analyses need to be completed, Clark says.
“The goals of this project are proof of concept that NPS receptor-targeted molecules can mitigate opioid seeking,” he says. “And whether these same molecules can reduce oxycodone taking and reduce the motivation to obtain oxycodone.”
Test agents for the research are obtained from a longtime collaborator, Scott Runyon, PhD, director of organic and mechanical chemistry at the Triangle Research Institute, headquartered in North Carolina.