Estrogen-dependent visceral hypersensitivity following stress in rats: An fMRI study.
We used functional MRI and a longitudinal design to investigate the brain mechanisms in a previously reported estrogen-dependent visceral hypersensitivity model. We hypothesized that noxious visceral stimulation would be associated with activation of the insula, anterior cingulate cortex, and amygdala, and that estrogen-dependent, stress-induced visceral hypersensitivity would both enhance activation of these regions and recruit activation of other brain areas mediating affect and reward processing. Ovariectomized rats were treated with estrogen (17 β-estradiol, E2) or vehicle (n = 5 per group) and scanned in a 7T MRI at three different time points: pre-stress (baseline), 2 days post-stress, and 18 days post-stress. Stress was induced via a forced-swim paradigm. In a separate group of ovariectomized rats, E2 treatment induced visceral hypersensitivity at the 2 days post-stress time point, and this hypersensitivity returned to baseline at the 18 days post-stress time point. Vehicle-treated rats show no hypersensitivity following stress. During the MRI scans, rats were exposed to noxious colorectal distention. Across groups and time points, noxious visceral stimulation led to activations in the insula, anterior cingulate, and left amygdala, parabrachial nuclei, and cerebellum. A group-by-time interaction was seen in the right amygdala, ventral striatum-pallidum, cerebellum, hippocampus, mediodorsal thalamus, and pontine nuclei. Closer inspection of the data revealed that vehicle-treated rats showed consistent activations and deactivations across time, whereas estrogen-treated animals showed minimal deactivation with noxious visceral stimulation. This unexpected finding suggests that E2 may dramatically alter visceral nociceptive processing in the brain following an acute stressor. This study is the first to examine estrogen-stress dependent interactions in response to noxious visceral stimulation using functional MRI. Future studies that include other control groups and larger sample sizes are needed to fully understand the interactions between sex hormones, stress, and noxious stimulation on brain activity.
Department of Neural and Pain Sciences, School of Dentistry, University of Maryland, Baltimore, MD, USA Center for Pain and the Brain, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, MA, USA Department of Anaesthesia, Harvard Medical School, Boston, MA, USA.
Catherine S
CS
Hubbard
Department of Neural and Pain Sciences, School of Dentistry, University of Maryland, Baltimore, MD, USA.
Jane M
JM
Karpowicz
Department of Neural and Pain Sciences, School of Dentistry, University of Maryland, Baltimore, MD, USA.
Andrew J
AJ
Furman
Department of Neural and Pain Sciences, School of Dentistry, University of Maryland, Baltimore, MD, USA Department of Anaesthesia, Harvard Medical School, Boston, MA, USA Department of Anatomy, Institute of Biomedical Science-III, University of Sao Paulo, Sao Paulo, Brazil.
Joyce Teixeira
JT
da Silva
Department of Neural and Pain Sciences, School of Dentistry, University of Maryland, Baltimore, MD, USA Center to Advance Chronic Pain Research, University of Maryland, Baltimore, MD, USA dseminowicz@umaryland.edu.
David A
DA
Seminowicz
Department of Neural and Pain Sciences, School of Dentistry, University of Maryland, Baltimore, MD, USA Center to Advance Chronic Pain Research, University of Maryland, Baltimore, MD, USA.
Richard J
RJ
Traub
D000818:Animals; D003106:Colon / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006930:Hyperalgesia / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D009043:Motor Activity / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013315:Stress, Psychological / Q000150:complications*; D014781:Viscera / Q000473:pathology* / Q000503:physiopathology
D004967:Estrogens
ACC; Forced-swim; amygdala; colorectal distension; functional MRI; hippocampus; insula; irritable bowel syndrome