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Amygdaloid Corticotropin Releasing Factor as the Key Mediator of Chronic Visceral Pain in Females with a History of Early Life Stress
Author(s) -
Prusator Dawn K,
Meerveld Beverley GreenwoodVan
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.720.7
Subject(s) - visceral pain , medicine , irritable bowel syndrome , abdominal pain , endocrinology , gastroenterology , receptor , nociception
In females. early life stress (ELS) has been identified as a risk factor for the development of functional pain disorders such as irritable bowel syndrome (IBS) in adults. Previously, our laboratory has shown that unpredictable ELS results in female specific heightened visceral pain behaviors in adulthood. The central amygdala (CeA) has been identified as a key brain nucleus in the processing of stress and pain, however, the role of the CeA in modulating pain following ELS has not been investigated. Therefore, we hypothesized that ELS increases visceral sensitivity in adulthood via altered CeA function, specifically through altered corticotropin releasing factor (CRF) expression. Neonatal rats underwent classical conditioning using unpredictable odor‐shock pairings or odor only as a control. In adulthood, CRF expression in the CeA was quantified via qRT‐PCR. CRF knockdown occurred via cannulae implanted into the CeA for infusion of antisense or random sense oligodeoxynucleotides (ASO/RSO n=6–7/group). Visceral sensitivity was assessed via visceromotor response (VMR) quantified as the number of abdominal contractions in response to graded pressures (0–60mmHg) of isobaric colorectal distension (CRD). The role of CRF receptor 1 was assessed via administration of a selective CRF receptor 1 antagonist CP 376395 5μg/0.5μl administered bilaterally (n=6/group). Expression of CRF was upregulated in the CeA following unpredictable ELS (p<0.01) compared to odor only controls. Administration of the RSO non‐targeting control sequence did not alter visceral hypersensitivity previously observed in the unpredictable group (60mmHg: 35.3±0.6) compared to odor only controls (26.2± 0.5). Knockdown of CRF in the CeA via ASO infusion significantly decreased the number of pain responses in unpredictable females as quantified by VMR to CRD (27.6±0.9, p< 0.01), while ASO treatment in the control group did not significantly alter pain responses (23.5±1.4). Administration of CRF1R antagonist mirrored the effects of CRF ASO infusion by significantly decreasing the VMR to CRD in adult females experiencing unpredictable ELS (26.8±1.1, p<0.01) to that of odor only control (27.0±1.1) In summary, this study suggests a novel consequence of ELS on visceral pain responses in adulthood that are centrally driven via CRF and directly related to the context, predictable or unpredictable, of the ELS experienced. Furthermore, this study identifies for the first time a mechanism by which females develop chronic visceral pain following ELS. Support or Funding Information This work was supported by a department of Veterans Affairs Merit Grant to BG‐VM #01BX001195