Perinatal fentanyl exposure leads to long-lasting impairments in somatosensory circuit function and behavior

One consequence of the opioid epidemic are the lasting neurodevelopmental sequelae afflicting children and adolescents exposed to opioids in the womb. The gravity of these consequences is further amplified by the COVID-19 pandemic, in which the use of synthetic opioids, including fentanyl, has increased among pregnant women. A translationally relevant and developmentally accurate preclinical model is needed to understand the behavioral, circuit, network, and molecular abnormalities resulting from fentanyl use during pregnancy. By employing a novel preclinical model of perinatal fentanyl exposure, our data reveal that fentanyl has several dose-dependent, developmental consequences to somatosensory function and behavior. First, newborn mice exhibit signs of withdrawal, and sensory-related deficits that extend at least to adolescence. As fentanyl exposure does not affect dams health or maternal behavior, these effects appear to result from the direct actions of perinatal fentanyl on the pups developing brain. At adolescence, exposed mice exhibited reduced adaptation to sensory stimuli, and a corresponding impairment in primary somatosensory (S1) function. Our in vitro electrophysiology data demonstrate that perinatal fentanyl leads to a long-lasting reduction in S1 synaptic excitation, as evidenced by decreases in excitatory release probability, NMDA receptor-mediated postsynaptic currents, and frequency of miniature excitatory postsynaptic currents, as well as increased frequency of miniature inhibitory postsynaptic currents. In contrast, anterior cingulate cortical neurons exhibit an opposite phenotype, with increased synaptic excitation in perinatal fentanyl exposed mice. Consistent with these synaptic changes, analysis of electrocorticograms revealed that exposed adolescent mice exhibited suppressed ketamine-evoked {gamma} oscillations. Morphological analysis of S1 pyramidal neurons from exposed mice indicate reduced dendritic complexity, dendritic length, and soma size. Further, exposed mice exhibited abnormal cortical mRNA expression of key receptors involved in synaptic transmission and neuronal growth and development, changes that were consistent with the electrophysiological and morphological changes. These findings demonstrate the lasting sequela of perinatal fentanyl exposure on sensory processing and function.