Centeno, M. V. | Search bioRxiv

bioRxiv2023

Long-range action of an HDAC inhibitor treats chronic pain in a spared nerve injury rat model

Histone deacetylase inhibitors (HDACi) that modulate epigenetic regulation and are approved for treating rare cancers have, in disease models, also been shown to mitigate neurological conditions, including chronic pain. They are of interest as non-opioid treatments, but achieving long-term efficacy with limited dosing has remained elusive. Here we utilize a triple combination formulation (TCF) comprised of a pan-HDACi vorinostat (Vo at its FDA-approved daily dose of 50mg/Kg), the caging agent 2-hydroxypropyl-{beta}-cyclodextrin (HPBCD) and polyethylene glycol (PEG) known to boost plasma and brain exposure and efficacy of Vo in mice and rats, of various ages, spared nerve injury (SNI) model of chronic neuropathic pain. Administration of the TCF (but not HPBCD and PEG) decreased mechanical allodynia for 4 weeks without antagonizing weight, anxiety, or mobility. This was achieved at less than 1% of the total dose of Vo approved for 4 weeks of tumor treatment and associated with decreased levels of major inflammatory markers and microglia in ipsilateral (but not contralateral) spinal cord regions. A single TCF injection was sufficient for 3-4 weeks of efficacy: this was mirrored in repeat injections, specific for the injured paw and not seen on sham treatment. Pharmacodynamics in an SNI mouse model suggested pain relief was sustained for days to weeks after Vo elimination. Doubling Vo in a single TCF injection proved effectiveness was limited to male rats, where the response amplitude tripled and remained effective for > 2 months, an efficacy that outperforms all currently available chronic pain pharmacotherapies. Together, these data suggest that through pharmacological modulation of Vo, the TCF enables single-dose effectiveness with extended action, reduces long-term HDACi dosage, and presents excellent potential to develop as a non-opioid treatment option for chronic pain.

neuroscience↗

bioRxiv2022

Pattern of Self-Administered Vapor Fentanyl Exposure Determines Long-term Behavior Consequences, in Mice with or without Neuropathic Pain

We studied the behavioral consequences of fentanyl vapor self-administration (SA) in mice with and without chronic neuropathic pain (one month after spared-nerve injury(SNI) model or sham injury). We assessed fentanyl consumption, motivation, and seeking during as well as anxiety, hyperactivity, immobility, and pain for two regimens of fentanyl SA: 1) Dose escalation, where over a 3-week period mice are exposed (daily 2-hour sessions) to escalating numbers of fentanyl puffs per active nosepoke (from 1 puff/active nosepoke for first 3 days, up to 6 puffs/active nosepoke in days 16-18). 2) Effort escalation, where over a 3-week period (daily 2-hour sessions) mice need to increase effort to acquire the same amount of fentanyl (fixed ratio 1 (FR) = 1 active nosepoke results in 1 fentanyl puff, while second and third week we use FR5 and FR10). We observe sex-, injury- and regimen-dependent differences in outcomes. Importantly the dose escalation regimen resulted in higher seeking behavior (post forced abstinence, context and cue driven nosepoking in the absence of fentanyl delivery), long lasting increased anxiety, immobility, and hyperactivity, as well as transient but full pain relief in SNI mice. Therefore, this regimen seems a better rodent model for translating outcomes to human chronic pain patients managed with opioids.

neuroscience↗