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Cited by 4Forensic Toxicology and Drug AnalysisNeurotransmitter Receptor Influence on BehaviorOpioid Use Disorder Treatment

The Synthetic Opioid Isotonitazene Induces Locomotor Activity and Reward Effects through Modulation of the Central Dopaminergic System in Mice

Tomiyama, Ken-ichi, Funada, Masahiko·2025·Toxicology and Applied Pharmacology
DOI 10.1016/j.taap.2025.117361
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Abstract

Synthetic opioids, which differ from fentanyl, have recently emerged as new psychoactive substances and pose public health concerns. The pharmacological effects and drug dependency of these benzimidazole-based opioids, also known as nitazenes, remain unclear. In this study, we examined the selectivity of opioid receptors, effects on motor activity, and expression of reward effects for isotonitazene, which has been detected in many poisonings and fatalities since 2019. Isotonitazene was most selective for the μ-receptor and exhibited more potent agonist effects, with an EC 50 of 0.02 nM, than morphine (EC 50 = 34 nM) and fentanyl (EC 50 = 4.0 nM). In ICR mice, isotonitazene (up to 0.05 mg/kg) increased the locomotor activity in a dose-dependent manner. This effect was significantly suppressed by pretreatment with the opioid receptor antagonists naloxone (3 mg/kg) and β-FNA (1 mg/kg), the dopamine D1 receptor antagonist SCH23390 (0.5 mg/kg), and dopamine D2 receptor antagonist raclopride (6 mg/kg). The reward effects of isotonitazene, evaluated using conditioned place preference (CPP) in mice, showed that conditioning with isotonitazene produced significant dose-dependent CPP scores. Microdialysis analysis also confirmed that the isotonitazene dose that induced CPP (0.05 mg/kg) significantly increased dopamine levels in the nucleus accumbens of mice. These results suggest that isotonitazene, similar to fentanyl and morphine, is a compound with a high risk of forming drug dependence and reward effects via the dopaminergic nervous system. This study provides foundational data for biological evaluation of other nitazene compounds.

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  • Isotonitazene is estimated at approximately 500 times the potency of morphine.

    “while isotonitazene is estimated at ~500 times the potency of morphine [12,34].”

    From Nitazenes: The Emergence of a Potent Synthetic Opioid Threat (2025) · cites this paper as [34]

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Authors
Tomiyama, K.-I., & Funada, M.
Affiliations
National Center of Neurology and Psychiatry (JP)
Corresponding author
Funada, Masahiko
ORCID
Funada, Masahiko
Venue
Toxicology and Applied Pharmacology
Publisher
Elsevier BV
Published
2025-07
Volume
500
Pages
117361
ISSN
0041-008X (ISSN-L)
DOI
10.1016/j.taap.2025.117361
OpenAlex
W4410051518
Cited by
4
References
41
Citations by year
2026: 3 · 2025: 1
FWCI
2.05
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Toxicology and Applied Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Ministry of Health, Labour and Welfare (23KC1002, 23KC2005)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
Keywords
isotonitazene, nitazenes, synthetic opioids, mu-opioid receptor selectivity, locomotor activity, reward, conditioned place preference, dopamine, nucleus accumbens, dopamine D1 receptor, dopamine D2 receptor, naloxone, fentanyl analogs, drug addiction
MeSH terms
Analgesics, Opioid, Animals, Behavior, Animal, Benzimidazoles, Dopamine, Dose-Response Relationship, Drug, Locomotion, Male, Mice, Inbred ICR, Narcotic Antagonists, Reward, Mice

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