Inhibitory transmission in the bed nucleus of the stria terminalis in male and female mice following morphine withdrawal

Addict Biol. 2020 May;25(3):e12748. doi: 10.1111/adb.12748. Epub 2019 Apr 9.


The United States is experiencing an opioid crisis imposing enormous fiscal and societal costs and driving the staggering overdose death rate. While prescription opioid analgesics are essential for treating acute pain, cessation of use in individuals with a physical dependence induces an aversive withdrawal syndrome that promotes continued drug use to alleviate/avoid these symptoms. Additionally, repeated bouts of withdrawal often lead to an increased propensity for relapse. Understanding the neurobiology underlying withdrawal is essential for providing novel treatment options to alleviate physiological and affective components accompanying the cessation of opiate use. Here, we administered morphine and precipitated withdrawal with naloxone to investigate behavioral and cellular responses in C57BL/6J male and female mice. Following 3 days of administration, both male and female mice demonstrated sensitized withdrawal symptoms. Since the bed nucleus of the stria terminalis (BNST) plays a role in mediating withdrawal-associated behaviors, we examined plastic changes in inhibitory synaptic transmission within this structure 24 hours following the final precipitated withdrawal. In male mice, morphine withdrawal increased spontaneous GABAergic signaling compared with controls. In contrast, morphine withdrawal decreased spontaneous GABAergic signaling in female mice. Intriguingly, these opposing GABAergic effects were contingent upon activity-dependent dynamics within the ex vivo slice. Our findings suggest that male and female mice exhibit some divergent cellular responses in the BNST following morphine withdrawal, and alterations in BNST inhibitory signaling may contribute to the expression of behaviors following opioid withdrawal.

Keywords: GABA; bed nucleus of the stria terminalis; morphine; opioids; sex differences; withdrawal.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Female
  • Inhibitory Postsynaptic Potentials / drug effects*
  • Male
  • Mice, Inbred C57BL
  • Miniature Postsynaptic Potentials / drug effects
  • Morphine / pharmacology*
  • Morphine Dependence
  • Naloxone / pharmacology*
  • Narcotic Antagonists / pharmacology*
  • Neural Inhibition / drug effects*
  • Neuronal Plasticity / drug effects
  • Patch-Clamp Techniques
  • Septal Nuclei / cytology
  • Septal Nuclei / drug effects*
  • Septal Nuclei / metabolism
  • Septal Nuclei / physiopathology
  • Substance Withdrawal Syndrome / etiology
  • Substance Withdrawal Syndrome / physiopathology*
  • Synaptic Transmission / drug effects*
  • gamma-Aminobutyric Acid / metabolism


  • Analgesics, Opioid
  • Narcotic Antagonists
  • Naloxone
  • gamma-Aminobutyric Acid
  • Morphine