Abstract
BackgroundEarly-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.MethodsWe 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.ResultsNS 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.ConclusionsThis 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.
Highlights
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
The glial excitatory amino acid transporters (EAATs), in particular, EAAT 1 and EAAT 2 are crucial in the maintenance of homeostasis within the glutamatergic synapse; their expression has been shown to be altered in chronic pain models [17, 18]
Early-life stress and estrous cycle-dependent variations in visceral sensitivity A two-way analysis of variance (ANOVA) analysis of threshold sensitivity revealed a significant effect of stress (F(1, 50) = 11.42, p < 0.01), estrous cycle (F(2, 50) = 6.847, p < 0.01), and an interaction effect of stress × estrous cycle (F(2, 50) = 5.561, p < 0.01, Fig. 1a, n = 9/10 per group)
Summary
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. We further investigate changes in visceral pain sensitivity and central glutamatergic systems in rats with respect to estrous cycle and ELS. Chronic pain syndromes such as irritable bowel syndrome (IBS), fibromyalgia, migraine, and interstitial cystitis display a striking female preponderance with females presenting at the clinic up to ten times more often than their male counterparts [1, 2]. Numerous studies in the rat have shown a decreased threshold and greater sensitivity in the proestrus phase; others have reported no difference between estrous stages [5, 11,12,13]. Pharmacological activation of these transporters has demonstrated therapeutic potential [17]
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