Sex Differences in Bed Nucleus of the Stria Terminalis Response to Calcitonin Gene-Related Peptide

Women are disproportionately affected by chronic pain, yet the neural mechanisms underlying sex differences in affective pain processing remain incompletely understood. The bed nucleus of the stria terminalis (BNST), a sexually dimorphic structure implicated in aversion and chronic pain, receives dense input from aversive calcitonin gene-related peptide (CGRP)-expressing neurons arising from the parabrachial nucleus (PBN). Although CGRP signaling has been implicated in sex differences in clinical pain conditions, whether CGRP transmission within the PBN[->]BNST pathway is sexually dimorphic has not been determined. Here, we tested the hypothesis that CGRP signaling in the BNST differs between sexes. Contrary to our prediction, PBN CGRP neurotransmitter release in the BNST was sex-independent. However, CGRP neuromodulation of BNST excitability exhibited sex-dependent features. While CGRP potentiated PBN[->]BNST glutamatergic signaling in both sexes, spontaneous inhibitory signaling was selectively increased in males. Together, these findings indicate that sex differences in this circuit arise not from differential peptide release, but from downstream modulation of inhibitory tone, biasing female BNST neurons toward greater excitation. Such circuit-specific sex differences may contribute to the enhanced susceptibility of females to affective components of chronic pain and highlight targets for sex-informed therapeutic interventions.