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Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in Brain Function and Behavior

Background Drug-evoked adaptations in the mesolimbic dopamine system drive opioid abuse and addiction, but these adaptations vary in magnitude and direction following different patterns of opioid exposure. Despite fundamental links between the pattern of drug exposure and abuse liability, few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. Methods In male and female mice, we first compared the behavioral consequences of chronic morphine exposure for one week, across multiple doses and with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with twice-daily naloxone injections, and used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. Results Continuous morphine exposure caused tolerance to both the antinociceptive and psychomotor-activating effects of morphine. In contrast, both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in the nucleus accumbens and dorsal striatum, dramatically increasing the number of differentially expressed transcripts and engaging unique signaling pathways. Conclusions These experiments indicate that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may therefore represent a strategy to minimize detrimental effects on brain reward circuits. This may in turn reduce the risk of progression from opioid use to abuse, promoting safer use of opioid-based treatments for clinical indications.