Notice of Special Interest (NOSI): Basic Research on Fentanyl and Synthetic Fentanyl Analogs: Signaling, Neurobiology, and Pharmacology
Notice Number:

Key Dates

Release Date:

March 24, 2021

First Available Due Date:
June 05, 2021
Expiration Date:
September 08, 2024

Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

Issued by

National Institute on Drug Abuse (NIDA)


This Notice informs potential applicants to the National Institute on Drug Abuse (NIDA) about a special interest in basic research on fentanyl and synthetic fentanyl analogs. Of particular interest is research that is focused on elucidating chemical, cellular, signaling, and neurobiological mechanisms underlying abuse potential, physical dependence, addiction liability and deaths due to overdose of fentanyl and fentanyl analogs.


Although over-prescription of opioid analgesics was the initial driver of the current opioid crisis, this was maintained and accelerated by a shift towards the use of potent synthetic opioids such as fentanyl and related analogs. Fentanyl is a clinically used opioid that is 50-100 times more potent than morphine and analogs such as carfentanyl can be 10,000 times more potent. The illicit use of fentanyl and the combination of fentanyl and fentanyl-related compounds with other illicit drugs, particularly CNS stimulants such as methamphetamine and cocaine, has resulted in a steep rise in drug overdoses and deaths. Fentanyl has been linked to two thirds of opioid overdose deaths and twice as many as heroin. Because of its high potency, fast onset and long duration, fentanyl overdoses are more difficult to reverse and often require multiple doses of naloxone. Respiratory depression produced by fentanyl is uniquely characterized by chest wall rigidity and laryngospasm, suggesting the involvement of other mechanisms. Although the primary mechanism by which fentanyl and analogs exert their pharmacological actions is through activation of G protein-coupled m-opioid receptors (MOR), it is recognized that unique pharmacological effects of MOR ligands may arise as a result of biased coupling to distinct signaling pathways or differential trafficking and signaling in subcellular compartments. There is little information regarding these cellular actions of fentanyl. Moreover, there is evidence that off-target interactions of fentanyl with monoamine transporters, serotonin receptors, dopamine receptors, noradrenergic and/or cholinergic systems may underlie a distinct profile of side effects, morbidity and mortality associated with fentanyl and synthetic-designer opioids. An additional gap in our basic knowledge relates to how chronic fentanyl use can be best transitioned to medication assisted therapy such as buprenorphine, which can pose the challenge of precipitating withdrawal. Enhanced understanding of the cellular pathways and neurocircuitry engaged by chronic fentanyl use can guide this transition. Finally, little is known about the genetic basis of sensitivity to fentanyl or epigenetic changes that may result from chronic use.

In view of the alarming increase in the use of non-pharmaceutical fentanyl and illicit synthetic fentanyl analogs, and the attendant deleterious social and medical consequences, there is an urgent need for multiple lines of fundamental research aimed at identifying and illuminating molecular, signaling, cellular, and circuit level mechanisms that contribute to the consequences of chronic use of this class of compounds. Knowledge gained from these studies should help inform research on potential targets and therapeutics strategies to address the problem of fentanyl, synthetic fentanyl analogs, and opioid use disorders.

Research Objectives

The goal of this announcement is to encourage basic preclinical research aimed at exploring the chemistry, pharmacology, genetic, molecular and neural systems mechanisms of actions of fentanyl and synthetic fentanyl analogs. Examples of research areas of interest include, but are not limited to:

  • Studies to determine the molecular interactions of fentanyl and fentanyl analogs with their targets and how these may be distinct from other opioids; structural features that influence binding at orthosteric or allosteric sites; intrinsic efficacy from agonism to antagonism; signaling pathway bias.
  • Biophysical, structural, and computational studies to elucidate differential receptor modulation by fentanyl and fentanyl analogs in comparison with non-fentanyl opioid ligands.
  • Application of novel and emerging target-identification and validation techniques to discover molecular targets that contribute to the exacerbated side effects of fentanyl and fentanyl analogs.
  • Studies on mechanisms that contribute to exacerbated side-effects, morbidity and mortality caused by fentanyl and fentanyl analogs when combined with methamphetamine, cocaine and related stimulants.
  • Studies on physicochemical, pharmacokinetic and pharmacodynamic mechanisms that contribute to toxicity of fentanyl and fentanyl analogs, particularly in combination with CNS stimulants.
  • Studies to elucidate cellular signaling and trafficking caused by fentanyl and fentanyl analogs that are distinct from other opioids.
  • Studies on rate of development and characteristics of physical dependence to fentanyl and fentanyl analogs.
  • Studies investigating the effects of fentanyl on epigenomic modifications, non-coding RNA regulation, or gene expression in CNS cells.
  • Comparative investigations of fentanyl and fentanyl analogs versus other abused substances in choice behavior, relative reinforcement, and the ability to reinforce associations with environmental stimuli that serve as cues prompting drug-taking behavior.
  • Studies to determine the role of fentanyl and fentanyl analogs in induction and maintenance of polysubstance use.
  • Development of analytic detection methods to identify fentanyl and fentanyl analogs in drug samples and biospecimens such as urine, blood, saliva, and sweat, including, rapid, point-of-use methods to be used in community settings and methods to detect multiple substances and metabolites from the same sample.
  • Elucidation of circuitry and neurocognitive systems engaged by fentanyl and fentanyl analogues after acute and chronic use, and withdrawal; or prenatal exposure due to maternal use.

Application and Submission Information

This notice applies to due dates on or after June 5, 2021 and subsequent receipt dates through September 7, 2024. 

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

  • PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
  • PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include “NOT-DA-21-033” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.


Please direct all inquiries to the contacts in Section VII of the listed funding opportunity announcements with the following additions/substitutions:

Scientific/Research Contact(s)

Kiran Vemuri, Ph.D.
National Institute on Drug Abuse (NIDA)

Telephone: 301-402-3396


Financial/Grants Management Contact(s)

Pamela G. Fleming
National Institute on Drug Abuse (NIDA)

Telephone: 301-480-1159


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices