Oxycodone‐induced Gene adaptations in the brain reward center in a murine Model of Neuropathic pain

Abstract

The long‐term use of opioids for the treatment of chronic pain can lead to physical dependence and transition to addiction. Recent studies from our group revealed that chronic neuropathic pain promotes several adaptations in the brain reward regions (Descalzi et al., Sci. Signaling, 2017). Here, we are using Next Generation RNA sequencing and upstream pathway analysis to gain insight on gene expression adaptations triggered by persistent exposure to oxycodone in the presence and in the absence of pain. To this extent, we employed the spared nerve injury model (SNI) of neuropathic pain in adult C57Bl/6 mice and assessed peripheral neuropathy symptoms for 9 weeks. We then applied an oxycodone misuse paradigm, where mice were treated daily with oxycodone for two weeks, and gene expression was monitored three weeks after oxycodone withdrawal. Mice were also assessed for emotional and pain‐related behaviors during the three‐week drug withdrawal period. Oxycodone treatment‐induced thermal hyperalgesia regardless of pain states, while withdrawal produced significant mechanical allodynia and deficits in social interaction. Using RNA Sequencing, we monitored changes in gene expression in the medial prefrontal cortex, the nucleus accumbens, and the ventral tegmental area. Although oxycodone treatment promotes mostly unique transcriptome profiles across brain regions, we observed similar downstream effectors and transcription factors to be affected in pain states when compared with non‐pain states. Furthermore, our findings suggest that chronic pain states exacerbate the behavioral and transcriptomic signatures of oxycodone withdrawal. Overall this work will provide new insights on the influence of long term pain in oxycodone‐induced plasticity in the brain reward center.Support or Funding Information5T32DA007135‐34, NIDA, R01 NS086444, R56 NS111351 NINDS, and P01 DA008227, NIDA