Disulfiram Abrogates Morphine Tolerance—A Possible Role of µ-Opioid Receptor-Related G-Protein Activation in the Striatum
Open accessAbstract
One of the key strategies for effective pain management involves delaying analgesic tolerance. Early clinical reports indicate an extraordinary effectiveness of off-label disulfiram—an agent designed for alcohol use disorder—in potentiating opioid analgesia and abrogation of tolerance. Our study aimed to determine whether sustained µ-opioid signaling upon disulfiram exposure contributes to these phenomena. Wistar rats were exposed to acute and chronic disulfiram and morphine cotreatment. Nociceptive thresholds were assessed with the mechanical Randal-Selitto and thermal tail-flick tests. µ-opioid receptor activation in brain structures important for pain processing was carried out with the [35S]GTPγS assay. The results suggest that disulfiram (12.5–50 mg/kg i.g.) augmented morphine antinociception and diminished morphine (25 mg/kg, i.g.) tolerance in a supraspinal, opioid-dependent manner. Disulfiram (25 mg/kg, i.g.) induced a transient enhancement of µ-opioid receptor activation in the periaqueductal gray matter (PAG), rostral ventromedial medulla (RVM), hypothalamus, prefrontal cortex and the dorsal striatum at day 1 of morphine treatment. Disulfiram rescued µ-opioid receptor signaling in the nucleus accumbens and caudate-putamen 14 days following morphine and disulfiram cotreatment. The results of this study suggest that striatal µ-opioid receptors may contribute to the abolition of morphine tolerance following concomitant treatment with disulfiram.
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DIS enhances μ-opioid receptor G-protein signaling, which could contribute to augmentation of morphine antinociception and abolition of morphine tolerance development.
“DIS enhances μ-opioid receptor G-protein signaling, which could, in part, contribute to the augmentation of morphine antinociception and abolition of morphine tolerance development.128”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [128]
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- Authors
- de Corde-Skurska, A., Krzascik, P., Lesniak, A., Sacharczuk, M., Nagraba, L., & Bujalska-Zadrozny, M.
- Affiliations
- Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Banacha 1b Str., 02-097 Warsaw, Poland
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Banacha 1b Str., 02-097 Warsaw, Poland
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences (PL)
- Department of Orthopaedics and Rehabilitation, Medical University of Warsaw, Bursztynowa 2 Str., 04-749 Warsaw, Poland
- ORCID
- Sacharczuk, Mariusz
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2021-04-14
- Volume
- 22
- Issue
- 8
- Pages
- 4057
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC8071001
- OpenAlex
- W3156230711
- Cited by
- 6
- References
- 76
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 2 · 2022: 1
- FWCI
- 0.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministry of Science and Higher Education in Poland (FW/N/13)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Keywords
- disulfiram, morphine tolerance, mu-opioid receptor, opioid analgesia, G protein signaling, dorsal striatum, periaqueductal gray, rostral ventromedial medulla, nucleus accumbens, caudate-putamen, nociception, analgesic tolerance
- MeSH terms
- Alcoholism, Analgesics, Opioid, Animals, Corpus Striatum, Disulfiram, Drug Tolerance, Humans, Male, Morphine, Receptors, Opioid, mu, GTP-Binding Proteins, Rats, Pain Management, Gray Matter
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