Withdrawal from opioid painkillers can produce short‐lived physical symptoms and protracted psychological symptoms including anxiety and depressive‐like states that often lead to opioid misuse and opioid use disorder (OUD). Studies testing the hypothesis that opioid withdrawal potentiates the reinforcing effects of opioid self‐administration (SA) are largely inconclusive and have focused on males. Although some clinical evidence indicates that women are more likely than men to misuse opioids to self‐medicate, preclinical studies in both sexes are lacking. Based on clinical reports, we hypothesized that withdrawal from escalating‐dose morphine injections that approximates a prescription painkiller regimen would lead to increased oxycodone SA to a greater extent in female compared to male rats. After escalating‐dose morphine (5–30 mg/kg or vehicle, twice/day for 12 days), rats underwent a 2‐week abstinence period during which withdrawal signs were measured. The impact of this treatment was assessed on oxycodone SA acquisition, maintenance, dose response, and progressive ratio responding, with additional analyses to compare sexes. We found that both sexes expressed somatic withdrawal, whereas only males demonstrated hyperalgesia in the warm water tail flick assay. During SA acquisition, males with prior morphine exposure took significantly more oxycodone than females. Finally, females with prior morphine exposure demonstrated the lowest motivation to SA oxycodone in the progressive ratio test. Contrary to our initial hypothesis, our findings suggest that prior opioid exposure increases vulnerability to initiate misuse more in males and decreases the reinforcing efficacy of oxycodone in females.

Background New treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development. Methods We screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964). Results In the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay. Conclusions These results suggest that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test.

IntroductionRates of relapse to drug use during abstinence are among the highest for opioid use disorder (OUD). In preclinical studies, reinstatement to drug-seeking has been extensively studied as a model of relapse–but the work has been primarily in males. We asked whether biological sex contributes to behaviors comprising self-administration of the prescription opioid oxycodone in rats, and we calculated the relative contribution of these behavioral measures to reinstatement in male and female rats.Materials and methodsRats were trained to self-administer oxycodone (8 days, training phase), after which we examined oxycodone self-administration behaviors for an additional 14 days under three conditions in male and female rats: short access (ShA, 1 h/d), long access (LgA, 6 h/d), and saline self-administration. All rats were then tested for cue-induced reinstatement of drug-seeking after a 14-d forced abstinence period. We quantified the # of infusions, front-loading of drug intake, non-reinforced lever pressing, inter-infusion intervals, escalation of intake, and reinstatement responding on the active lever.ResultsBoth male and female rats in LgA and ShA conditions escalated oxycodone intake to a similar extent. However, males had higher levels of non-reinforced responding than females under LgA conditions, and females had greater levels of reinstatement responding than males. We then correlated each addiction-related measure listed above with reinstatement responding in males and females and ranked their respective relative contributions. Although the majority of behavioral measures associated with oxycodone self-administration did not show sex differences on their own, when analyzed together using partial least squares regression, their relative contributions to reinstatement were sex-dependent. Front-loading behavior was calculated to have the highest relative contribution to reinstatement in both sexes, with long and short inter-infusion intervals having the second greatest contribution in females and males, respectively.DiscussionOur results demonstrate sex differences in some oxycodone self-administration measures. More importantly, we demonstrate that a sex- dependent constellation of self-administration behaviors can predict the magnitude of reinstatement, which holds great promise for relapse prevention in people.