Sunday, May 5, 2024
5/5/2024
Project Summary/Abstract Female patients have increased pain sensitivity, increased risk for developing chronic pain, and increased risk for adverse reactions to opioids. Despite these sex differences, many preclinical pain studies focus solely on males. I will address this gap by investigating central pain circuitry in male and female mice, and examine the role of circuitry sex differences in driving chronic pain. The parabrachial nucleus (PB) and bed nucleus of the stria terminalis (BNST), two structures involved in the affective processing of pain ( ‘unpleasant’ emotional perception of pain), share reciprocal connections. Calcitonin gene related peptide (CGRP), a neuropeptide released from the PB in the BNST, is also linked with affective pain processing. The BNST is a highly sexually dimrophic brain structure; it is possible that sex differences in chronic pain susceptibility arise due to sex differences in BNST CGRP pain circuitry. Consistent with this, my preliminary findings in mice show that CGRP differentially alters tonic BNST inhibition in females versus males; CGRP decreases BNST inhibitory tone in females, and increases BNST inhibitory tone in males. CGRP may exert its sex-dependent effect through KCC, a potassium / chloride cotransporter, thereby regulating the inhibitory potential of GABA signaling. Additionally, PB CGRP may be acting on different BNST subpopulations between males and females, including those that project back to the parabrachial nucleus (aversive BNSTGlut¿PB and rewarding BNSTGABA¿PB). Whereas PB CGRP inputs preferentially target inhibitory BNST neurons in males, my preliminary findings suggest excitatory BNST neurons are preferentially targeted in females. Based on these findings, my hypothesis is that PB CGRP release exerts sex-dependent effects on BNST projection neurons, such that CGRP potentiates KCC2 to increase inhibition of BNSTGABA¿PB neurons in males, while inhibiting KCC2 to disinhibit BNSTGlut¿PB neurons in females. I will test predictions that corroborate this hypothesis with three specific aims. First, I will determine whether sex-differences in CGRP’s effect on BNST inhibitory tone are due to modulation of KCC2. Second, I will test whether PB inputs preferentially target BNSTGABA¿PB neurons in males, and BNSTGlut¿PB neurons in females. Third, I will test whether BNST CGRP signaling is causally involved in behavioral sex differences in chronic neuropathic pain. These aims will clarify sex-differences in BNST CGRP signaling, and its role in the affective component of pain. This project is part of a training plan designed to equip me with skills necessary for a career as a physician neuroscientist. I will carry out this proposal under the mentorship of my Sponsor Dr. Asaf Keller, a sensory perception expert, and thesis committee (Table 1), experts in pain and addiction. This mentoring team will oversee my scientific development and facilitate my progess in achieving these aims and my career goals.
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