title: Sex-dependent activity of the spinal excitatory amino acid transporter: Role of estrous cycle.
abstract: Females are more likely to experience visceral pain than males, yet mechanisms underlying this sex bias are not fully elucidated. Moreover, pain sensitivity can change throughout the menstrual cycle. Alterations in the glutamatergic system have been implicated in several pain-disorders; however, whether these are sex-dependent is unclear. Thus, we aimed to investigate sex differences in the spinal cord glutamate uptake and how it varies across the estrous cycle. The activity of the glutamate transporters, excitatory amino acid transporters (EAATs) was assessed using an ex vivo aspartate radioactive uptake assay in the lumbosacral spinal cord in Sprague-Dawley male and female rats. The gene expression of EAATs, glutamate receptor subunits NR1 and NR2B and the estrogen receptors ERα & ERβ in the spinal cord were also analyzed. EAAT activity was lower in females, particularly during the estrus phase, and this was the only cycle stage that was responsive to the pharmacological effects of the EAATs activator riluzole. Interestingly, EAAT1 mRNA expression was lower in high-estrogen and high-ERα states compared to diestrus in females. We conclude that the Spinal EAAT activity in females is different to that in males, and varies across the estrous cycle. Furthermore, the expression levels of estrogen receptors also showed a cycle-dependent pattern that may affect EAATs function and expression.
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Ireland.
authors.forename: Jahangir
authors.initials: J
authors.lastname: Sajjad
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Institute, University College Cork, Ireland.
authors.forename: Valeria D
authors.initials: VD
authors.lastname: Felice
authors.affiliation: APC Microbiome Institute, University College Cork, Ireland.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Golubeva
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Institute, University College Cork, Ireland.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Institute, University College Cork, Ireland. Electronic address: somahony@ucc.ie.
authors.forename: Siobhain M
authors.initials: SM
authors.lastname: O'Mahony
mesh_terms: D000818:Animals; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D030762:Estrous Cycle / Q000378:metabolism*; D005260:Female; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D050491:Glutamate Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid
keywords: EAATs; estrogen; estrous cycle; glutamatergic system; spinal cord; visceral pain