title: Estrous cycle influences excitatory amino acid transport and visceral pain sensitivity in the rat: effects of early-life stress.
abstract: BACKGROUND
  Early-life stress (ELS) is a recognized risk factor for chronic pain disorders, and females appear to be more sensitive to the negative effects of stress. Moreover, estrous cycle-related fluctuations in estrogen levels have been linked with alternating pain sensitivity. Aberrant central circuitry involving both the anterior cingulate cortex (ACC) and the lumbosacral spinal cord has also been implicated in the modulation of visceral pain in clinical and preclinical studies. Here we further investigate changes in visceral pain sensitivity and central glutamatergic systems in rats with respect to estrous cycle and ELS.
  
  
  METHODS
  We investigated visceral sensitivity in adult female Sprague-Dawley rats, which had undergone maternal separation (MS) in early life or remained non-separated (NS), by performing colorectal distension (CRD). We also assessed excitatory amino acid uptake through excitatory amino acid transporters (EAATs) in the lumbosacral spinal cord and ACC.
  
  
  RESULTS
  NS animals in proestrus and estrus exhibited reduced EAAT uptake and decreased threshold to CRD. Moreover, total pain behaviors were increased in these stages. MS rats exhibited lower pain thresholds and higher total pain behaviors to CRD across all stages of the estrous cycle. Interestingly, cortical EAAT function in MS rats was inhibited in the low estrogen state-an effect completely opposite to that seen in NS rats.
  
  
  CONCLUSIONS
  This data confirms that estrous cycle and ELS are significant factors in visceral sensitivity and fluctuations in EAAT function may be a perpetuating factor mediating central sensitization.
authors.affiliation: Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.|Present Address: Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK USA.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Moloney
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Office 4.113, Western Gateway Building, Cork, Ireland.
authors.forename: Jahangir
authors.initials: J
authors.lastname: Sajjad
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Office 4.113, Western Gateway Building, Cork, Ireland.
authors.forename: Tara
authors.initials: T
authors.lastname: Foley
authors.affiliation: Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.
authors.forename: Valeria D
authors.initials: VD
authors.lastname: Felice
authors.affiliation: Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
authors.affiliation: Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Anatomy and Neuroscience, University College Cork, Office 4.113, Western Gateway Building, Cork, Ireland.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.affiliation: Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Anatomy and Neuroscience, University College Cork, Office 4.113, Western Gateway Building, Cork, Ireland.
authors.forename: Siobhain M
authors.initials: SM
authors.lastname: O'Mahony
keywords: Aspartate uptake; Colorectal distension; Early-life stress; Excitatory amino acid transporter; Glutamatergic system; Visceral pain