The ultrasonic vocalization (USV) syllable profile during neonatal opioid withdrawal and a kappa opioid receptor component to increased USV emissions in female mice

Kelly K Wingfield; Teodora Misic; Kaahini Jain; Carly S McDermott; Nalia M Abney; Kayla T Richardson; Mia B Rubman; Jacob A Beierle; Sophia A Miracle; Emma J Sandago; Britahny M Baskin; William B Lynch; Kristyn N Borrelli; Emily J Yao; Elisha M Wachman; Camron D Bryant

doi:10.1007/s00213-024-06694-7

The ultrasonic vocalization (USV) syllable profile during neonatal opioid withdrawal and a kappa opioid receptor component to increased USV emissions in female mice

Psychopharmacology (Berl). 2024 Sep 30. doi: 10.1007/s00213-024-06694-7. Online ahead of print.

Authors

Kelly K Wingfield^{1

2}, Teodora Misic¹, Kaahini Jain¹, Carly S McDermott¹, Nalia M Abney¹, Kayla T Richardson^{1

3}, Mia B Rubman⁴, Jacob A Beierle^{2

5}, Sophia A Miracle^{1

6}, Emma J Sandago¹, Britahny M Baskin^{1

7}, William B Lynch^{1

5

6}, Kristyn N Borrelli^{1

2

5

6}, Emily J Yao¹, Elisha M Wachman⁸, Camron D Bryant⁹

Affiliations

¹ Laboratory of Addiction Genetics, Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, 140 The Fenway, Boston, MA, USA.
² T32 Biomolecular Pharmacology Training Program, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
³ Post-Baccalaureate Research Education Program, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
⁴ NIH/NIDA Summer Undergraduate Fellowship Program, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
⁵ Transformative Training Program in Addiction Science, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
⁶ Graduate Program for Neuroscience, Boston University, Boston, MA, USA.
⁷ T32 Training Program on Development of Medications for Substance Use Disorders Fellowship, Center for Drug Discovery, Northeastern University, Boston, MA, USA.
⁸ Department of Pediatrics, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA.
⁹ Laboratory of Addiction Genetics, Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, 140 The Fenway, Boston, MA, USA. c.bryant@northeastern.edu.

PMID: 39348003
DOI: 10.1007/s00213-024-06694-7

Abstract

Rationale: Opioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments.

Objectives: We sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal.

Methods: We employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal.

Results: On P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor (Oprk1), which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice.

Conclusions: We identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.

Keywords: Brainstem; Emotional-affective withdrawal; Kappa opioid receptor; Morphine; Neonatal opioid withdrawal syndrome; RNA-seq; Sex differences; Spectrotemporal profile; Transcriptome; Ultrasonic vocalizations.

Abstract

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