(692.19) A novel HDAC1/2 inhibitor alleviates physical and emotional symptoms associated with spontaneous oxycodone withdrawal in neuropathic pain mice

Poster Board Number: B41

Kerri Pryce (Icahn School of Medicine at Mount Sinai), Aarthi Ramakrishnan (Icahn School of Medicine at Mount Sinai), Hope Kronnman (Icahn School of Medicine at Mount Sinai), Andrew Nicolais (Icahn School of Medicine at Mount Sinai), Claire Polizu (Icahn School of Medicine at Mount Sinai), Anne Ruiz (Icahn School of Medicine at Mount Sinai), Randal Serafini (Icahn School of Medicine at Mount Sinai), Sevasti Gaspari (Icahn School of Medicine at Mount Sinai), Catherine Pena (Princeton Neuroscience Institute), Angelica Torres-Berrio (Icahn School of Medicine at Mount Sinai, Icahn School of Medicine at Mount Sinai), Vassiliki Mitsi (Icahn School of Medicine at Mount Sinai), Matthew Darpe (3Regenancy Pharmaceuticals), LI Shen (Icahn School of Medicine at Mount Sinai), Eric Nestler (Icahn School of Medicine at Mount Sinai), Venetia Zachariou (Icahn School of Medicine at Mount Sinai)

The development of physical dependence and addiction disorders due to misuse of opioid analgesics is a major concern with pain therapeutics. In this study, we developed a mouse model of oxycodone misuse in order to gain insight into genes and molecular pathways in reward-related brain regions that are affected by prolonged exposure to oxycodone and subsequent withdrawal in the presence or absence of chronic neuropathic pain. RNA-sequencing (RNA-seq) and bioinformatic analyses revealed that oxycodone withdrawal alone triggers robust gene expression adaptations in the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and ventral tegmental area (VTA), with numerous genes and pathways selectively affected by oxycodone withdrawal under peripheral nerve injury states. Our pathway analysis predicted that histone deacetylase 1 (HDAC1), an epigenetic modifier with a prominent role in striatal plasticity, is a top upstream regulator in opioid withdrawal in both the NAc and mPFC. Indeed, treatment with the novel HDAC1/2 inhibitor RCY1305 attenuated behavioral manifestations of oxycodone withdrawal, with the drug being more efficacious under states of neuropathic pain. Our studies also suggest that RCY1305 treated mice did not develop conditional place preference. Since RCY1305 displays antiallodynic actions with no rewarding effects in models of neuropathic pain, inhibition of HDAC1/2 may provide an avenue for chronic pain patients dependent on opioids to transition to non-opioid analgesics. Overall, our study highlights transcriptomic events in components of the reward circuitry associated with oxycodone withdrawal under pain-naïve and prolonged neuropathic pain states, thereby providing information on possible new targets for the treatment of physical dependence to opioids and transitioning individuals to non-opioid medications for chronic pain management.

5T32DA007135-34, R01 NS086444, NINDS R01 NS111351 NINDS, P01 DA008227 NIDA