RT Journal Article
SR Electronic
T1 Sex Differences in Behavioral and Brainstem Transcriptomic Neuroadaptations following Neonatal Opioid Exposure in Outbred Mice
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0143-21.2021
DO 10.1523/ENEURO.0143-21.2021
VO 8
IS 5
A1 Kristyn N. Borrelli
A1 Emily J. Yao
A1 William W. Yen
A1 Rhushikesh A. Phadke
A1 Qiu T. Ruan
A1 Melanie M. Chen
A1 Julia C. Kelliher
A1 Carly R. Langan
A1 Julia L. Scotellaro
A1 Richard K. Babbs
A1 Jacob C. Beierle
A1 Ryan W. Logan
A1 William Evan Johnson
A1 Elisha M. Wachman
A1 Alberto Cruz-Martín
A1 Camron D. Bryant
YR 2021
UL http://www.eneuro.org/content/8/5/ENEURO.0143-21.2021.abstract
AB The opioid epidemic led to an increase in the number of neonatal opioid withdrawal syndrome (NOWS) cases in infants born to opioid-dependent mothers. Hallmark features of NOWS include weight loss, severe irritability, respiratory problems, and sleep fragmentation. Mouse models provide an opportunity to identify brain mechanisms that contribute to NOWS. Neonatal outbred Swiss Webster Cartworth Farms White (CFW) mice were administered morphine (15 mg/kg, s.c.) twice daily from postnatal day 1 (P1) to P14, an approximation of the third trimester of human gestation. Female and male mice underwent behavioral testing on P7 and P14 to determine the impact of opioid exposure on anxiety and pain sensitivity. Ultrasonic vocalizations (USVs) and daily body weights were also recorded. Brainstems containing pons and medulla were collected during morphine withdrawal on P14 for RNA sequencing. Morphine induced weight loss from P2 to P14, which persisted during adolescence (P21) and adulthood (P50). USVs markedly increased at P7 in females, emerging earlier than males. On P7 and P14, both morphine-exposed female and male mice displayed hyperalgesia on the hot plate and tail-flick assays, with females showing greater hyperalgesia than males. Morphine-exposed mice exhibited increased anxiety-like behavior in the open-field arena on P21. Transcriptome analysis of the brainstem, an area implicated in opioid withdrawal and NOWS, identified pathways enriched for noradrenergic signaling in females and males. We also found sex-specific pathways related to mitochondrial function and neurodevelopment in females and circadian entrainment in males. Sex-specific transcriptomic neuroadaptations implicate unique neurobiological mechanisms underlying NOWS-like behaviors.