Tran, S. C. | bioRxiv Science

bioRxiv2025

Chronic pain increases sensitivity to pain-induced reinstatement of ethanol seeking in male mice

Alcohol use disorder (AUD) and chronic pain are complex and debilitating conditions that are highly comorbid. Greater than 50% of individuals with AUD have chronic pain. Clinical data suggest that people with chronic pain are more likely to report using alcohol to manage chronic pain, and that magnitude of pain is correlated with relapse probability after a period of abstinence. These data led to the hypothesis that pain can drive ethanol seeking and reinstatement in a rodent model of chronic neuropathic pain. A conditioned place preference (CPP) paradigm was used to model ethanol seeking in male C57BL6J mice with a spared nerve injury (SNI). Mice were conditioned with doses of ethanol previously found to reverse pain behavior (0.5g/kg). Mice with and without SNI showed similar magnitudes of ethanol CPP and rates of extinction. To investigate pain-induced relapse-related behavior, mice underwent reinstatement testing following painful mechanical stimulation which was delivered at either a "moderate" or "high" intensity immediately prior to return to the CPP apparatus. "Moderate" painful hindpaw stimulation reinstated ethanol seeking behavior in SNI-injured, but not sham, mice, while "high" intensity stimulation reinstated ethanol seeking in mice regardless of injury status. These data suggest that males in chronic pain are more susceptible reinstatement of ethanol seeking following a painful experience.

animal behavior and cognition↗

bioRxiv2020

Dengue and Zika virus infection are impaired by small molecule ER proteostasis regulator 147 in an ATF6-independent manner

Flaviviruses, including Dengue and Zika, are widespread human pathogens, however, no broadly active therapeutics exist to fight infection. Here, we establish the recently discovered pharmacologic modulator of ER proteostasis 147 as an effective host-centered antiviral strategy. Compound 147 reduces infection by attenuating viral replication without causing toxicity in host cells. 147 is a preferential activator of the ATF6 pathway of the unfolded protein response, which requires targeting of cysteine residues primarily on protein disulfide isomerases (PDIs). We find that the antiviral activity of 147 is independent of ATF6 induction but does require modification of reactive thiols on protein targets. Targeting PDIs using RNAi and other PDI small molecule inhibitors was unable to recapitulate the antiviral effects, suggesting additional identified protein targets of 147 may mediate the activity. Importantly, 147 can impair infection of multiple strains of Dengue and Zika virus, indicating that it is suitable as a broad-spectrum antiviral agent.

biochemistry↗