Opioid exposure and withdrawal both cause adaptations in brain circuits that may contribute to abuse liability. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological impact. In this study, we compared cellular and synaptic adaptations in the nucleus accumbens shell caused by morphine exposure that was either continuous or interrupted by daily bouts of naloxone-precipitated withdrawal. At the behavioral level, continuous morphine administration caused psychomotor tolerance, which was reversed when the continuity of morphine action was interrupted by naloxone-precipitated withdrawal. Using ex vivo slice electrophysiology in female and male mice, we investigated how these patterns of morphine administration altered intrinsic excitability and synaptic plasticity of medium spiny neurons (MSNs) expressing the D1 or D2 dopamine receptor. We found that morphine-evoked adaptations at excitatory synapses were predominately conserved between patterns of administration, but there were divergent effects on inhibitory synapses and the subsequent balance between excitatory and inhibitory synaptic input. Overall, our data suggest that continuous morphine administration produces adaptations that dampen the output of D1-MSNs, which are canonically thought to promote reward-related behaviors. Interruption of otherwise continuous morphine exposure does not dampen D1-MSN functional output to the same extent, which may enhance behavioral responses to subsequent opioid exposure. Our findings support the hypothesis that maintaining continuity of opioid administration could be an effective therapeutic strategy to minimize the vulnerability to opioid use disorders.
|Original language||English (US)|
|Number of pages||11|
|Journal||Journal of Neuroscience|
|State||Published - Jan 11 2023|
Bibliographical noteFunding Information:
Received Mar. 11, 2022; revised Oct. 14, 2022; accepted Nov. 12, 2022. Author contributions: E.M.L. and P.E.R. designed research; E.M.L., E.A.G., L.L.B., and J.S. performed research; E.M.L. analyzed data; E.M.L. and P.E.R. wrote the paper. This work was supported by the University of Minnesota Discovery, Research, and InnoVation Economy initiative and by National Institutes of Health Grants K99 DA052624 (E.M.L.), R00 DA037279 (P.E.R.), and R01 DA048946 (P.E.R.). We thank David Leipold and Kerry Trotter for technical assistance. The authors declare no competing financial interests. Correspondence should be addressed to Patrick E. Rothwell at email@example.com. https://doi.org/10.1523/JNEUROSCI.0595-22.2022 Copyright © 2023 the authors
© 2023 the authors.
- nucleus accumbens
- opioid withdrawal
- synaptic plasticity
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't