Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury.
Kerri D PryceRandal A SerafiniAarthi RamakrishnanAndrew NicolaisIlinca M GiosanClaire PolizuAngelica Torres-BerrioSreeya VuppalaHope KronmanAnne RuizSevasti GaspariCatherine Jensen PeñaFarhana SaklothVasiliki MitsiJohn van DuzerRalph MazitschekMatthew JarpeLi ShenEric J NestlerVenetia ZachariouPublished in: Nature neuroscience (2023)
The development of physical dependence and addiction disorders due to misuse of opioid analgesics is a major concern with pain therapeutics. We developed a mouse model of oxycodone exposure and subsequent withdrawal in the presence or absence of chronic neuropathic pain. Oxycodone withdrawal alone triggered robust gene expression adaptations in the nucleus accumbens, medial prefrontal cortex and ventral tegmental area, with numerous genes and pathways selectively affected by oxycodone withdrawal in mice with peripheral nerve injury. Pathway analysis predicted that histone deacetylase (HDAC) 1 is a top upstream regulator in opioid withdrawal in nucleus accumbens and medial prefrontal cortex. The novel HDAC1/HDAC2 inhibitor, Regenacy Brain Class I HDAC Inhibitor (RBC1HI), attenuated behavioral manifestations of oxycodone withdrawal, especially in mice with neuropathic pain. These findings suggest that inhibition of HDAC1/HDAC2 may provide an avenue for patients with chronic pain who are dependent on opioids to transition to non-opioid analgesics.
Keyphrases
- histone deacetylase
- chronic pain
- neuropathic pain
- prefrontal cortex
- peripheral nerve
- pain management
- spinal cord
- gene expression
- mouse model
- spinal cord injury
- dna methylation
- adipose tissue
- mental health
- skeletal muscle
- transcription factor
- genome wide
- physical activity
- oxidative stress
- high fat diet induced
- resting state
- insulin resistance
- subarachnoid hemorrhage
- type diabetes