Fentanyl exposure during preconception and gestation permanently dysregulates endogenous opioid peptides and sympathoadrenal-medullary axis in the offspring

In the United States, the alarming increase in opioid use disorder diagnoses during pregnancy in the last decade has increased the incidence of neonatal opioid withdrawal syndrome (NOWS). Although 8 per 1,000 newborns are diagnosed with NOWS each year, the lack of prospective studies is a roadblock in the development of approaches to reduce adverse health outcomes in this vulnerable population. This study used a preclinical model to assess short- and long-term effects of preconceptional and gestational fentanyl (FEN) exposure on morphometrics, hormonal plasma profile, and sensitivity to opioid re-exposure in the offspring. Sprague Dawley female rats self-administered FEN citrate [fixed-ratio 1 (FR1), 2.5 μg/kg] or vehicle (NaCl 0.9%) during preconception and until gestational day 21. In utero fentanyl exposure (IUFE) did not influence neonatal weight and morphometrics; however, IUFE pups exhibited a higher frequency of behaviors indicative of somatic withdrawal compared with controls (CTLs). In male and female weanlings, IUFE induced the dysregulation of endogenous opioid peptides (EOPs) and increased metanephrine levels compared with CTL counterparts. However, only adult females with IUFE showed increased EOPs and metanephrine levels, FEN-induced hyperalgesia, and greater FEN-induced hypotensive and bradycardic effects compared with CTL counterparts. This preclinical model suggests a long-lasting association between IUFE-induced neuroendocrine dysregulation and adverse effects of opioid re-exposure in female offspring.