Disulfiram abrogates morphine tolerance—a possible role of μ‐opioid receptor‐related g‐protein activation in the striatum

Abstract

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.