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. 2016 Jul 14:7:33.
doi: 10.1186/s13293-016-0086-6. eCollection 2016.

Estrous cycle influences excitatory amino acid transport and visceral pain sensitivity in the rat: effects of early-life stress

Rachel D Moloney #  1   2   3 , Jahangir Sajjad #  4 , Tara Foley  4 , Valeria D Felice  1 , Timothy G Dinan  1   2 , John F Cryan  1   4 , Siobhain M O'Mahony  1   4
Affiliations

Estrous cycle influences excitatory amino acid transport and visceral pain sensitivity in the rat: effects of early-life stress

Rachel D Moloney et al. Biol Sex Differ. .

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.

Keywords: Aspartate uptake; Colorectal distension; Early-life stress; Excitatory amino acid transporter; Glutamatergic system; Visceral pain.

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Figures

Fig. 1
Fig. 1
Early-life stress and estrous cycle-dependent variations in visceral sensitivity. Maternally separated (MS) animals exhibit visceral hypersensitivity with a significantly lower threshold of visceral distension required for identifiable abdominal contraction (a) and increased total pain behaviors (b) compared to non-separated controls (NS) (**p < 0.01 non-sep vs mat-sep, ## p < 0.01, #### p < 0.0001 vs met/die non-sep, n = 9–10/group)
Fig. 2
Fig. 2
Early-life stress and estrous cycle-dependent variations in spinal EAAT function. Estrous cycle plays a role in EAAT function in the lumbosacral spinal cord with both the estrus and proestrus phases of the cycle inducing significant reductions in EAAT function (# p < 0.05, ## p < 0.01 vs met/die non-sep, n = 10/group)
Fig. 3
Fig. 3
Early-life stress and estrous cycle-dependent variations in central EAAT function. Estrous cycle and early-life stress play a role in EAAT function in the anterior cingulate cortex with both the estrus and proestrus phases of the cycle inducing significant reductions in EAAT function in NS rats (#### p < 0.0001 vs met/die non-sep, n = 10/group) and estrus and proestrus phases showing increased EAAT function in MS rats ($ p < 0.05, $$ p < 0.01 vs met/die mat-sep, n = 10/group)
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