Neurobiological characterization of sex differences in somatic, motivational, and emotional aspects of opiate withdrawal

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Opioid use disorder (OUD) has reached epidemic proportions, with over 1,000 daily emergency room visits, and claiming ~130 lives per day, to opioid overdoses in the U.S. The Covid-19 pandemic has only made matters worse. Opioids significantly affect men and women differently, yet most of what is known about opioid dependence and withdrawal has been derived from studies exclusively in men and then extrapolated to women; and parameters used to delineate the neurobiology of opioid withdrawal (OW) syndrome have been developed using male subjects. This represents significant gaps in our understanding; filling such gaps will help devise better, sex- based, treatment strategies. Our long-term objective is to understand basic behavioral and neural processes underlying OW that will inform the development of strategies to improve treatment outcomes that someday could facilitate the matching of patients to treatments. To this end, the research Aims outlined in this application will begin to fill three important gaps in our knowledge. First Gap: Studies of OUD show that women suffer from more severe emotional and physical withdrawal as compared to men, yet the few basic studies assessing sex differences in OW show inconsistent results. We will characterize sex differences in the onset, expression, and duration of somatic, motivational, and emotional symptoms of acute and protracted OW syndrome in male and female rats over the course of the estrous cycle. We hypothesize that severity and persistence of OW symptoms vary as a function of gonadal hormone status in males and females. Second Gap: Severity and mismanagement of OW symptoms are primary contributors to attrition from treatment. Women are at an increased risk for dropping out; and available treatments have unwanted effects, especially when prescribed, or combined, with benzodiazepines, a therapeutic highly prescribed to, and utilized by, women. Thus, new medication approaches are much needed. We will begin to fill this gap by assessing the efficacy of ketamine (KET) in alleviating OW symptomatology. We hypothesize that KET will be efficacious in ameliorating OW symptomatology. Third Gap: Knowledge of the neural mechanism(s) underlying OW has been derived from studies in males, showing that cAMP-activated-CREB is essential for alterations in gene expression that precipitate OW. The effects of OW on cAMP-PKA-CREB activity in the tail of the ventral tegmental area/rostromedial tegmental nucleus (tVTA/RMTg), a brain region we first described to respond to chronic drug exposure and aversive stimuli, are just beginning, and only one study from our lab has been performed in females. We will begin establishing causal relationships by examining the functional significance of CREB expression in the tVTA/RMTg during OW, selectively regulating CREB activity in tVTA/RMTg neurons to assess the severity and persistence of OW symptoms in male and female rats using viral vector gene-transfer technology. The research proposed here will begin to provide a greater understanding of the systemic effects and fundamental pathways underlying sex differences in OW.