Early-life stress induces visceral hypersensitivity in mice

Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Ireland.
Neuroscience Letters (Impact Factor: 2.03). 03/2012; 512(2):99-102. DOI: 10.1016/j.neulet.2012.01.066
Source: PubMed


Early-life stress is a risk factor for irritable bowel syndrome (IBS), a common and debilitating functional gastrointestinal disorder that is often co-morbid with stress-related psychiatric disorders. In the rat, maternal separation (MS) stress has been shown to induce visceral hypersensitivity in adulthood and thus has become a useful model of IBS. However, development of mouse models of maternal separation has been difficult. Given the advent of transgenic mouse technology, such models would be useful to further our understanding of the pathophysiology of IBS and to develop new pharmacological treatments. Thus, the present study aimed to develop a mouse model of MS stress-induced visceral hyperalgesia as measured using manometric recordings of colorectal distension (CRD). Moreover, since the GABA(B) receptor has been reported to play a role in pain processes, we also assessed its role in visceral nociception using novel GABA(B(1b)) receptor subunit knockout mice. CRD was performed in adult male wildtype and GABA(B(1b)) receptor knockout mice that had undergone unpredictable MS combined with unpredictable maternal stress (MSUS) from postnatal day 1 through 14 (PND 1-14). MSUS induced visceral hypersensitivity in both wildtype and GABA(B(1b)) receptor knockout mice when compared with non-stressed mice. Wildtype and GABA(B(1b)) receptor knockout mice did not differ in baseline or stress-induced visceral sensitivity. To the best of our knowledge, this is the first study to show that early-life stress induces visceral hypersensitivity in a mouse model. These findings may provide a novel mouse model of visceral hypersensitivity which may aid our understanding of its underlying mechanisms in future studies.

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    • "The maternal separation model is not only used to study psychiatric disease including schizophrenia (Ellenbroek et al., 1998), depression (MacQueen et al., 2003, O'Mahony et al., 2009, Desbonnet et al., 2010, RM et al., 2013) and cognitive deficits (Pusceddu et al., 2015) but also disorders of communication between the brain and the gut as in irritable bowel syndrome where stress is known to play a role (O'Mahony et al., 2009, O'Malley et al., 2011, Moloney et al., 2012, Felice et al., 2014, Kennedy et al., 2014b, Hyland et al., 2015). The interpretation of these results from behavioural tests is confounded by the fact that maternally separated rats display exaggerated fear and stress responses which can be difficult to disentangle from other behavioural outputs. "
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    ABSTRACT: The prenatal and postnatal early-life periods are both dynamic and vulnerable windows for brain development. During these important neurodevelopmental phases, essential processes and structures are established. Exposure to adverse events that interfere with this critical sequence of events confers a high risk for the subsequent emergence of mental illness later in life. It is increasingly accepted that the gastrointestinal microbiota contributes substantially to shaping the development of the central nervous system. Conversely, several studies have shown that early-life events can also impact on this gut community. Due to the bidirectional communication between the gut and the brain, it is possible that aberrant situations affecting either organ in early life can impact on the other. Studies have now shown that deviations from the gold standard trajectory of gut microbiota establishment and development in early life can lead to not only disorders of the gastrointestinal tract but also complex metabolic and immune disorders. These are being extended to disorders of the central nervous system and understanding how the gut microbiome shapes brain and behavior during early life is an important new frontier in neuroscience.
    Neuroscience 10/2015; DOI:10.1016/j.neuroscience.2015.09.068 · 3.36 Impact Factor
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    • " ; Lippmann et al . 2007 ; Aisa et al . 2008 ; Gareau et al . 2008 ; Oines et al . 2012 ) , anxiety - like behaviour ( Varghese et al . 2006 ; Lippmann et al . 2007 ; Desbonnet et al . 2010 ; O ' Mahony et al . 2011 ; Abelaira et al . 2013 ; Li et al . 2013 ) , visceral hypersensitivity ( Eutamene et al . 2007 ; O ' Mahony et al . 2011 ; Moloney et al . 2012 ; Felice et al . 2014 ) and altered cholinergic activity in the gut ( Gareau et al . 2007b ; O ' Malley et al . 2010 ) accompanied by increased intestinal permeability ( Söderholm et al . 2002 ; Barreau et al . 2004a ; García - R ´ odenas et al . 2006 ; Eutamene et al . 2007 ; Gareau et al . 2007b ; Oines et al . 2012 ) . Maternally sep"
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    ABSTRACT: The gut-brain axis is the bi-directional communication between the gut and the brain which occurs through multiple pathways that include hormonal, neural and immune mediators. The signals along this axis can originate in the gut, the brain, or both, with the objective of maintaining normal gut function and appropriate behavior. In recent years, the study of gut microbiota has become one of the most important areas in biomedical research. Attention has focused on the role of gut microbiota in determining normal gut physiology and immunity, and more recently on its role as modulator of host behavior ("microbiota-gut-brain axis"). We therefore review the literature on the role of gut microbiota in gut homeostasis and link it with mechanisms that could influence behavior. We discuss the association of dysbiosis with disease with particular focus on functional bowel disorders and its relation to psychological stress. This is of particular interest as exposure to stressors has long been known to increase susceptibility to and severity of gastrointestinal diseases.
    The Journal of Physiology 04/2014; 592(14). DOI:10.1113/jphysiol.2014.273995 · 5.04 Impact Factor
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    • "Previous animal studies have demonstrated that acute and chronic stress is associated with the development of allodynia, hyperalgesia or unaltered nociceptive sensitivity [17,18,39,40]. For example, 10–20 min forced swimming daily for 3 days induces hyperalgesia to thermal and chemical stimuli 8 to 9 days after the last swim session [17]. "
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    ABSTRACT: Clinical studies indicate that patients with post-traumatic stress disorder (PTSD) frequently share comorbidity with numerous chronic pain conditions. However, the sustained effects of PTSD-like stress over time on visceral nociception and hyperalgesia have been rarely studied, and the underlying mechanisms of stress-induced modulation of visceral hyperalgesia remain elusive. The purpose of this study was to investigate the characterization of visceral nociception and hyperalgesia over time in rats exposed to PTSD-like stress, and to explore the potential role of protein kinase C gamma (PKCgamma) in mediating visceral hyperalgesia following exposure to PTSD-like stress. On day 1, the rats exposed to single-prolonged stress (SPS, an established animal model for PTSD) exhibited an analgesic response and its visceromotor response (VMR) to graded colorectal distention (CRD) at 40 and 60 mmHg was reduced compared with the control group (all P < 0.05). On day 6, the VMR returned to the baseline value. However, as early as 7 days after SPS, VMR dramatically increased compared with its baseline value and that in the controls (all P < 0.001) and this increase persisted for 28 days, with the peak on day 9. Abdominal withdrawal reflex (AWR) scores were higher in SPS rats than in controls on days 7, 9, 14, 21 and 28 (all P < 0.001). Intrathecal administration of GF109203X (an inhibitor of PKC gamma), attenuated the SPS-induced increase in both VMR and AWR scores on days 7, 14, 21 and 28 (all P < 0.05). PKCgamma protein expression determined by immunofluorescence was reduced in the spinal cord within 3 days after the exposure to SPS (P < 0.01), which returned to normal levels between days 4 and 6, and significantly increased from day 7, and this increase was maintained on days 14, 21, and 28 (all P < 0.001), with the peak on day 9. In addition, Western blotting showed a consistent trend in the changes of PKCgamma protein expression. The modified SPS alters visceral sensitivity to CRD, and contributes to the maintenance of visceral hyperalgesia, which is associated with enhanced PKCgamma expression in the spinal cord. Functional blockade of the PKCgamma receptors attenuates SPS-induced visceral hyperalgesia. Thus, the present study identifies a specific molecular mechanism for visceral hyperalgesia which may pave the way for novel therapeutic strategies for PTSD-like conditions.
    Molecular Pain 07/2013; 9(1):35. DOI:10.1186/1744-8069-9-35 · 3.65 Impact Factor
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