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Opioid-Induced Hyperalgesia Is Associated with Dysregulation of Circadian Rhythm and Adaptive Immune Pathways in the Mouse Trigeminal Ganglia and Nucleus Accumbens


The benefits of opioid-based treatments to mitigate chronic pain can be hindered by the side effects of opioid-induced hyperalgesia (OIH) that can lead to higher consumption and risk of addiction. The present study advances the understanding of the molecular mechanisms associated with OIH by comparing mice presenting OIH symptoms in response to chronic morphine exposure (OIH treatment) relative to control mice (CON treatment). Using RNA-Seq profiles, gene networks were inferred in the trigeminal ganglia (TG), a central nervous system region associated with pain signaling, and in the nucleus accumbens (NAc), a region associated with reward dependency. The biological process of nucleic acid processing was over-represented among the 122 genes that exhibited a region-dependent treatment effect. Within the 187 genes that exhibited a region-independent treatment effect, circadian rhythm processes were enriched among the genes over-expressed in OIH relative to CON mice. This enrichment was supported by the differential expression of the period circadian clock 2 and 3 genes (Per2 and Per3). Transcriptional regulators in the PAR bZip family that are influenced by the circadian clock and that modulate neurotransmission associated with pain and drug addiction were also over-expressed in OIH relative to CON mice. Also notable was the under-expression in OIH relative to CON mice of the Toll-like receptor, nuclear factor-kappa beta, and interferon gamma genes and enrichment of the adaptive immune processes. The results from the present study offer insights to advance the effective use of opioids for pain management while minimizing hyperalgesia.

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We would like to thank Dr. Dennis Grayson for helpful discussion regarding experimental procedures and manuscript preparation. We are also grateful to Ying Chen for helping us with the RNA isolation and Hyeonsoo Jeong for preliminary data evaluation. Laura Moye is a member of the UIC Graduate Program in Neuroscience.


This study was funded by the National Institute of Health (grant numbers P30 DA018310-14 (SRZ, BS, JS), and DA031243 (AP)), the Department of Defense (grant number PR100085 (AP)), and US Department of Agriculture NIFA ILLU-538-909.

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Correspondence to Sandra L. Rodriguez-Zas.

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Zhang, P., Moye, L.S., Southey, B.R. et al. Opioid-Induced Hyperalgesia Is Associated with Dysregulation of Circadian Rhythm and Adaptive Immune Pathways in the Mouse Trigeminal Ganglia and Nucleus Accumbens. Mol Neurobiol 56, 7929–7949 (2019).

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  • Opioid-induced hyperalgesia
  • Morphine
  • RNA-Seq
  • Circadian rhythm
  • Adaptive immune response