Disulfiram Abrogates Morphine Tolerance—A Possible Role of µ-Opioid Receptor-Related G-Protein Activation in the Striatum

Autor: Anna de Corde-Skurska, Pawel Krzascik, Anna Lesniak, Mariusz Sacharczuk, Lukasz Nagraba, Magdalena Bujalska-Zadrozny
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: International Journal of Molecular Sciences, Vol 22, Iss 8, p 4057 (2021)
Druh dokumentu: article
ISSN: 1422-0067
1661-6596
DOI: 10.3390/ijms22084057
Popis: 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.
Databáze: Directory of Open Access Journals
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