Papers of the Week

Diagnoses of maternal opioid use disorder (MOUD) at delivery increased more than 500% between 1999 and 2017 in the United States. Today, cases of in utero opioid exposure due to MOUD exceed cases of the most common birth defects, including cleft lip, cleft palate, clubfoot, and Down syndrome, combined. Children exposed to opioids in utero are at increased risk of adverse childhood experiences (ACEs) due to parental care being compromised by SUDs. These ACEs include abuse, neglect, loss of a parent from death or incarceration, parental divorce, and household domestic violence. Altered sensitivity to opioid analgesia later in life is one potential outcome shared by in utero opioid exposure and ACEs that may contribute to poorly controlled pain and increased risk of opioid addiction. Studies using rat models of prenatal opioid exposure (POE) or early life adversity (ELA) have shown that each decreases opioid-induced antinociception long after exposure has ceased. However, the contributions of POE and ELA, alone and in combination, to opioid analgesic response in humans remains unknown. In this study, we used a rodent model of combined POE and ELA to disambiguate their long-term effects more quickly and with greater experimental control than human studies. We hypothesized that combined POE and ELA will decrease morphine-induced antinociception in adolescence relative to POE or ELA alone. We used a two-by-two between-subjects factorial design in which timed-pregnant Long-Evans rats were exposed to morphine (15 mg/kg/day; "POE" group) or saline ("vehicle" group) via subcutaneous osmotic minipump from gestation day 9 until delivery. Litters were fostered to untreated dams then randomly assigned to normal housing or ELA conditions using a limited bedding and nesting procedure from postnatal days 3-11. Morphine-induced antinociception was measured between postnatal days 30 and 54 using a warm-water tail withdrawal (WWTW) assay. Cumulative dose-response of morphine-induced antinociception was determined on test day 0 (1.0-30 mg/kg morphine, s.c.) and test day 13 (3.0-100 mg/kg, s.c.). On test days 1-12, rats were dosed with 18 mg/kg, s.c., every 12 hours, and WWTW was conducted on odd test days. Interesting, preliminary results of this ongoing study indicate that morphine-induced antinociception was enhanced on test day 0 in POE + normal-housed males (n = 2). These rats exhibited 100% maximum possible effect (MPE) and significantly higher potency (mean ED50=5.96 mg/kg; 95% CI = -12.12, 24.05), while mean MPE for the other groups (n=2-3) was less than 70% and mean ED50>17 mg/kg. Males exhibited partial tolerance throughout the 12-day chronic morphine treatment period. In the POE + normal-housed males, MPE decreased from 100% on test day 1 to 58% on test day 11. For the remaining groups, MPE decreased from 44-57% on test day 1 to 12-23% on test day 11. Morphine was more potent in the POE + normal-housed males on test day 13 (mean ED50=66.21 mg/kg; 95% CI = -281.6, 414) than in other males (mean ED50>104.4 mg/kg). No clear group effect was observed in females. These unexpected results suggest a complex sex-dependent interaction between POE and ELA on opioid antinociception.