Antinociceptive and discriminative stimulus effects of six novel psychoactive opioid substances in male rats
Open accessAbstract
Compounds with novel or fentanyl-like structures continue to appear on the illicit drug market and have been responsible for fatalities, yet there are limited preclinical pharmacological data available to evaluate the risk of these compounds to public health. The purpose of the present study was to examine acetyl fentanyl, butyryl fentanyl, 3,4-dichloro-N-[[1-(dimethylamino)cyclohexyl]methyl]benzamide (AH-7921), 1-cyclohexyl-4-(1,2-diphenylethyl)piperazine (MT-45), 4-chloro-N-[1-(2-phenylethyl)-2-piperidinylidene]-benzenesulfonamide (W-15), and 4-chloro-N-[1-[2-(4-nitrophenyl)ethyl]-2-piperidinylidene]-benzenesulfonamide (W-18) for their relative potency to reference opioids and their susceptibility to naltrexone antagonism using the 55 o C warm-water, tail-withdrawal assay of antinociception and a morphine drug discrimination assay in male, Sprague-Dawley rats. In the antinociception assay, groups of 8 rats per drug were placed into restraining tubes, their tails were immersed into 40 o or 55 o C water, and the latency for tail withdrawal was measured with a cutoff time of 15 seconds. In the drug discrimination assay, rats (n = 11) were trained to discriminate between 3.2 mg/kg morphine and saline, subcutaneously, in a two-choice, drug discrimination procedure under a fixed ratio-5 schedule of sucrose pellet delivery. Morphine, fentanyl, and four of the synthetic opioids dose dependently produced antinociception and fully substituted for morphine in the drug discrimination assay with the following rank order of potency: fentanyl > butyryl fentanyl > acetyl fentanyl > AH-7921 > MT45 > morphine. All drugs that produced antinociception or morphine-like discriminative stimulus effects were blocked by naltrexone. W-15 and W-18 did not show antinociceptive or morphine-like discriminative stimulus effects at the doses tested supporting a lack of opioid activity for these two compounds. These findings suggest that butyryl fentanyl, acetyl fentanyl, AH-7941, and MT-45 have abuse liability like other opioid agonists. SIGNIFICANCE STATEMENT: As novel psychoactive substances appear on the illicit drug market, preclinical pharmacological testing is required to assist law enforcement, medical professionals, and legal regulators with decisions about potential public health risks. In this study, four synthetic opioids, acetyl fentanyl, butyryl fentanyl, AH-7921, and MT-45 produced effects similar to fentanyl and morphine and were blocked by naltrexone. These data suggest the four synthetic opioids possess similar abuse liability risks as typical opioid agonists.
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Naloxone behaves as a competitive opioid receptor antagonist; therefore, its final effect depends on the relative antagonist/agonist ratio of concentrations in the brain areas controlling the different functions.
“It should be stressed that naloxone behaves as a competitive opioid receptor antagonist; therefore, its final effect depends on the relative antagonist/agonist ratio of concentrations in the brain areas controlling the different functions (Nakamura et al., 2020; Walker et al., 2021).”
From Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization (2024) · cites this paper as Walker et al., 2021
The Results and Discussion passages (page unavailable) describe dose-dependent antagonism by naltrexone, not naloxone. A search for naloxone and for antagonist/agonist concentration ratios in brain areas found no passage addressing either part of the attributed claim. (LLM, conf=0.78)
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- Authors
- Walker, E. A., Chambers, C., Korber, M. G., Tella, S. R., Prioleau, C., & Fang, L.
- Affiliations
- United States Department of Justice (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 379
- Issue
- 1
- Pages
- 1-11
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC8626635
- OpenAlex
- W3179876017
- Cited by
- 19
- References
- 43
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 5
- FWCI
- 0.95
- Type
- journal article
- Language
- en
- Update notices
- erratum (2022-02-01)
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Justice
- National Institute on Drug Abuse (P30DA013429)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- antinociception, discriminative stimulus, opioid analgesia, healthcare workers, asymptomatic infection, COVID-19 pandemic, SARS-CoV-2 antibodies, seroprevalence, occupational exposure, infection control, hospital departments
- MeSH terms
- Analgesics, Opioid, Animals, Central Nervous System Agents, Discrimination Learning, Dose-Response Relationship, Drug, Male, Pain Measurement, Psychotropic Drugs, Reaction Time, Rats, Sprague-Dawley, Rats
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