SEX-SPECIFIC REGULATION OF PAIN: A NOVEL ROLE FOR DOPAMINE AND CORTICOTROPIN-RELEASING FACTOR SIGNALING IN THE MIDBRAIN AND EXTENDED AMYGDALA Public Deposited

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  • March 2, 2021
Creator
  • Yu, Waylin
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • Chronic pain is the leading cause of disability and health care access in the United States. Sex differences in perception, response, and pathological susceptibility are common features of pain, with women being disproportionately affected and inadequately treated for pain across the lifespan. The neural mechanisms that contribute to these outcomes remain poorly understood, as female subjects have historically been underrepresented in pain research. The overarching goal of this dissertation is to identify the neurocircuit mechanisms of pain, with special emphasis on two regions of sex-specific pain modulation: the ventrolateral periaqueductal gray/dorsal raphe (vlPAG/DR) and the bed nucleus of stria terminalis (BNST). We first demonstrate a role for vlPAG/DR dopamine (DA) neurons in adaptive responses to pain, where activation of vlPAG/DR DA+ projections to the BNST reduces nociceptive sensitivity in male mice and increases locomotion in female mice. Deletion of the DA rate-limiting enzyme tyrosine hydroxylase (Th) in vlPAG/DR mitigates these behaviors, with vlPAG/DR DA+-BNST physiology supporting a key role for DA transmission in sex-specific function. We next characterize the contributions of corticotropin-releasing factor (CRF) in the BNST, as DA and CRF interactions in the BNST have been posited to impact pain. Robust in vivo recruitment of BNST CRF+ neurons was observed during exposure to a nociceptive stimulus, with male and female mice exhibiting distinct magnitude and synchronization in neuronal responses. We then show that genetic deletion of Crf in the BNST reduces nociceptive sensitivity for both sexes and increases paw attending responses in female mice. Finally, we discuss the implications of these novel pain mechanisms on drug use, citing results that illustrate the consequences of local Th and Crf deletion on morphine and alcohol treatment. Collectively, these findings establish a role for vlPAG/DR DA+ and BNST CRF+ neurons in the sex-specific expression of pain, highlighting promising new targets to achieve pain relief and counteract maladaptive drug use with precision medicine approaches.
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Advisor
  • Kash, Thomas L
  • Song, Juan
  • Nackley, Andrea G
  • Reissner, Kathryn J
  • McElligott, Zoe A
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2020
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