Persons suffering from opioid use disorder (OUD) experience long‐lasting dysphoric symptoms well into extended periods of withdrawal. This protracted withdrawal syndrome is notably characterized by heightened anxiety and hyperkatifeia. Here, we investigated if an exacerbated withdrawal model of acute morphine dependence results in lasting behavioral adaptation 6 weeks into forced abstinence in C57BL/6J mice. We found that our exacerbated morphine withdrawal paradigm produced distinct alterations in behavior in elevated plus maze (EPM), open field, and social interaction tests in male and female mice. Following protracted withdrawal male mice showed enhanced exploration of the open arms of the EPM, reduced latency to enter the corner of the OF, and a social interaction deficit. In contrast, female mice showed enhanced thigmotaxis in the OF. In both sexes, protracted withdrawal enhanced locomotor behavior in response to subsequent morphine challenge, albeit at different doses. These findings will be relevant for future investigation examining the neural mechanisms underlying these behaviors and will aid in uncovering physiological sex differences in response to opioid withdrawal.

Stress can drive adaptive changes to maintain survival during threatening stimuli. Chronic stress exposure, however, may result in pathological adaptations. A key neurotransmitter involved in stress signaling is norepinephrine. Previous studies show that stress elevates norepinephrine levels in the bed nucleus of the stria terminalis (BNST), a critical node regulating anxiety and upstream of stress responses. Here, we use mice expressing channelrhodopsin in norepinephrine neurons to selectively activate terminals in the BNST, and measure norepinephrine release with fast-scan cyclic voltammetry. Mice exposed to a single restraint session show an identical norepinephrine release profile compared to that of unexposed mice. Mice experiencing five days of restraint stress, however, show elevated norepinephrine release across multiple stimulation parameters, and reduced sensitivity to the α 2 -adrenergic receptor antagonist idazoxan. These data are the first to examine norepinephrine release in the BNST to tonic and phasic stimulation frequencies, and confirm that repeated stress alters autoreceptor sensitivity.

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103)Persons suffering from opioid use disorder (OUD) experience long-lasting dysphoric symptoms well into extended periods of withdrawal. This protracted withdrawal syndrome is notably characterized by heightened anxiety. Here we investigate if an exacerbated withdrawal model of acute morphine dependence results in lasting behavioral adaptation 6 weeks into forced abstinence. We found that our exacerbated morphine withdrawal paradigm produced distinct impairments in elevated-plus maze, open field, and social interaction tests in male and female mice. These findings will be relevant for future investigation examining the neural mechanisms underlying these behaviors, and will aid in uncovering physiological sex differences in response to opioid withdrawal.

The opioid epidemic has increased dramatically over the last few decades resulting in many suffering from opioid use disorder (OUD). The prevalence of opioids and opioid overdose has been driven by the development of new synthetic opioids, increased availability of prescription opioids, and more recently, the COVID-19 pandemic. As we see increased in exposure to opioids, the United States has also seen increases in the frequency of instances of Narcan (naloxone) administration as a life saving measure for respiratory depression, and, thus, consequently, naloxone-precipitated withdrawal. Sleep dysregulation is one of the main symptoms of OUD and opioid withdrawal syndrome, and therefore should be a key facet of animal models of OUD. Here we examine the effect of precipitated and spontaneous morphine withdrawal on sleep behaviors in C57BL/6J. We find that morphine administration and withdrawal dysregulates sleep, however not equally across morphine exposure paradigms and not qualitatively the same across sexes. Furthermore, many environmental triggers promote relapse to drug seeking/taking behavior, and the stress of disrupted sleep may fall into that category. We find that sleep deprivation dysregulates sleep in mice that had previous opioid withdrawal experience. These data suggest that the 3-day precipitated withdrawal paradigm has the most profound effects on opioid induced sleep dysregulation, and that further validate the construct of the 3-day precipitated withdrawal model as a model for opioid dependence and OUD.