Abstract 2143 Fentanyl and Xylazine Co-Use Induces Liver Dysfunction

The use of pan-proteasome inhibitors, such as those used for human cancer therapies, has been linked to development of painful peripheral neuropathy.Moreover, other studies suggest that low concentrations of these proteasome inhibitors result in reduced pain sensitivity leaving a gap in our understanding of the function of proteasomes in peripheral nerves.We recently identified the neuronal membrane proteasome (NMP) in a subpopulation of somatosensory neurons whose activity is involved in mediating pain sensitivity acutely.Here we treat mice with intradermal paw injections of the NMP inhibitor, Biotin epoxomicin (BE), over 4 weeks and use behavioral assays to test for pain sensitivity as well as biochemical approaches to investigate nerve ending degeneration in paw skin of treated mice.We demonstrate that sensitivity to painful pinprick stimuli is reduced at 2 hours following injection of BE, and 1 week later this change in sensitivity returns to baseline.These results were consistently observed over 4 consecutive weeks of treatment with 1 injection of BE per week.We show that BE injected into the paw skin remains local and is not detectable in the sciatic nerve or spinal cord.Moreover, no nerve ending degeneration or sensorimotor behavior alterations were observed after 4 weeks of BE treatment.Taken together, these data demonstrate that local NMP inhibition using BE can transiently reduce pain sensitivity without causing nerve ending neuropathy or sensorimotor behavior alterations and point to the NMP as a therapeutic target for pain modulation.