Corticotropin-Releasing Factor Neurons in the Bed Nucleus of the Stria Terminalis Differentially Influence Pain Processing and Modulation in Male and Female Mice

Abstract

The bed nucleus of the stria terminalis (BNST) plays an emerging yet understudied role in pain. Corticotropin-releasing factor (CRF) is an important source of pain modulation in the BNST, with local pharmacological inhibition of CRF receptors impacting both the sensory and affective components of pain. Knowledge on how pain dynamically engages CRF neurons in the BNST and is influenced by intra-BNST production of CRF remains unknown. In the present study, we utilized in vivo calcium imaging to show robust and synchronized recruitment of BNSTCRF+ neurons during acute exposure to noxious heat. Distinct patterns of recruitment were observed by sex, with males exhibiting a greater magnitude of heat responsive activity in BNSTCRF+ neurons than females. We then established the necessity of CRF for intact pain behaviors by genetically deleting Crf in the BNST, which reduced thermal and mechanical nociceptive sensitivity for both sexes, and increased paw attending responses to thermal nociception in female mice, suggesting a divergent role for CRF with respect to pain-related affective-motivational behaviors. Together, these findings demonstrate that CRF in the BNST contributes to multiple facets of the pain experience and may play a key role in the sex-specific expression of pain-related behaviors.