• Corticotropin-releasing hormone
• Early - life stress
• Irritable bowel syndrome
• Maternal separation
• Visceral hypersensitivity

• 23K06902 Japan Society for the Promotion of Science
• 20356688 Japan Agency for Medical Research and Development
• Tokutei Brain-Gut R1-2 Smoking Research Foundation

• Stress
• dynorphin
• electrophysiology
• pain
• superficial dorsal horn

• Animals
• Female
• Dynorphins/metabolism
• Mice
• Male
• Stress, Psychological/physiopathology
• Stress, Psychological/metabolism
• Excitatory Postsynaptic Potentials/physiology
• Posterior Horn Cells/physiology
• Interneurons/physiology
• Animals, Newborn
• Mice, Inbred C57BL
• Sex Characteristics
• Inhibitory Postsynaptic Potentials/physiology

• R01 NS080889 NINDS NIH HHS

• Constipation
• Gastrointestinal motility
• Gut microbiome
• Gut-brain axis
• Irritable bowel syndrome
• Vagus nerve stimulation

• Mice
• Animals
• Irritable Bowel Syndrome/therapy
• Irritable Bowel Syndrome/microbiology
• Vagus Nerve Stimulation
• RNA, Ribosomal, 16S
• Mice, Inbred C57BL
• Disease Models, Animal
• Constipation/etiology
• Constipation/therapy
• Water
• Vagus Nerve

• development
• early life stress
• glutamate
• hippocampus
• synapses

• Animals
• Male
• Mice
• Animals, Newborn
• Hippocampus/metabolism
• Stress, Psychological/metabolism
• Synapses
• Stress, Physiological
• Receptors, AMPA/metabolism

• WE.03-2018-01 Alzheimer Nederland
• Center for Urban Mental Health
• ZonMw MODEM
• WE.09-2022-01 Alzheimer Nederland

• Rats
• Female
• Animals
• Urinary Bladder
• Calcitonin Gene-Related Peptide
• Irritable Bowel Syndrome/drug therapy
• Visceral Pain/drug therapy
• Rats, Sprague-Dawley
• Colon
• Analgesics/pharmacology
• Analgesics/therapeutic use
• Disease Models, Animal

Neuropathic pain since early diabetes swamps patients' lives, and diabetes mellitus has become an increasingly worldwide epidemic. No agent, so far, can terminate the ongoing diabetes. Therefore, strategies that delay the process and the further complications are preferred, such as diabetic neuropathic pain (DNP). Dysfunction of ion channels is generally accepted as the central mechanism of diabetic associated neuropathy, of which hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channel has been verified the involvement of neuropathic pain in dorsal root ganglion (DRG) neurons. Riluzole is a benzothiazole compound with neuroprotective properties on intervention to various ion channels, including hyperpolarization-activated voltage-dependent channels. To investigate the effect of riluzole within lumbar (L3-5) DRG neurons from DNP models, streptozocin (STZ, 70 mg/kg) injection was recruited subcutaneously followed by paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL), which both show significant reduction, whilst relieved by riluzole (4 mg/kg/d) administration, which was performed once daily for 7 consecutive days for 14 days. HCN2 expression was also decreased in line with alleviated behavioral tests. Our results indicate riluzole as the alleviator to STZ-induced DNP with involvement of downregulated HCN2 in lumbar DRG by continual systemic administration in rats.

Early life stress (ELS) disposes to functional gastrointestinal diseases in adult, such as irritable bowel syndrome (IBS). Maternal separation (MS) is a well-known animal model of IBS and has been shown to induce visceral hypersensitivity in adult rats and mice. However, to the best of our knowledge, it has not been reported whether MS induces visceral hypersensitivity in young mice, such as the post-weaning mice. Moreover, the method for evaluation of visceral sensitivity also has not been described. Accordingly, the present study aims to evaluate the visceral sensitivity caused by MS in post-weaning mice and develop a novel and small size distention balloon for assessment of visceral sensitivity of such mice. Male pups of C57BL/6 mice were randomly divided into two groups, MS (n = 12) and non-separation (NS) (n = 10). MS pups were separated from the dams through postnatal days (PND) 2 to 14, while NS pups were undisturbed. After, all pups stayed with respective dams and were weaned at PND 22. Visceral sensitivity was evaluated by colorectal distention (CRD) with a novel and small size distention balloon at PND 25. The threshold of abdominal withdrawal reflex (AWR) scores were significantly lower in MS than NS. In addition, AWR scores at different pressures of CRD were significantly higher in MS than NS. The results demonstrate that MS induced visceral hypersensitivity in post-weaning mice. The designed small size distention balloon for evaluation of visceral sensitivity is of significance to further study the pathophysiology of IBS from early life to adulthood.

• C-Fos
• EphB2
• PTSD
• SPS
• Spinal cord
• visceral pain

• Animals
• Hyperalgesia/genetics
• Hyperalgesia/metabolism
• Male
• Proto-Oncogene Proteins c-fos/metabolism
• RNA, Messenger/metabolism
• Rats
• Rats, Sprague-Dawley
• Receptor, EphB2/genetics
• Receptor, EphB2/metabolism
• Spinal Cord/metabolism
• Stress, Psychological
• Visceral Pain/genetics
• Visceral Pain/metabolism

• Anterior cingulate cortex
• Central sensitization
• Chronic pain
• Lactates

• Glutamate toxicity
• Glutamatergic system
• Gulf War illness
• Therapy

• Animals
• Brain/metabolism
• Brain/physiopathology
• Diet Therapy
• Disease Management
• Glutamic Acid/metabolism
• Gulf War
• Humans
• Persian Gulf Syndrome/complications
• Persian Gulf Syndrome/metabolism
• Persian Gulf Syndrome/physiopathology
• Persian Gulf Syndrome/therapy
• Synapses/metabolism
• Synapses/pathology

• environment
• hospital
• maternal separation
• nociception
• prematurity

Early-life stress (ES) is an emerging risk factor for later life development of Alzheimer’s disease (AD). We have previously shown that ES modulates amyloid-beta pathology and the microglial response to it in the APPswe/PS1dE9 mouse model. Because astrocytes are key players in the pathogenesis of AD, we studied here if and how ES affects astrocytes in wildtype (WT) and APP/PS1 mice and how these relate to the previously reported amyloid pathology and microglial profile.

We induced ES by limiting nesting and bedding material from postnatal days (P) 2–9. We studied in WT mice (at P9, P30, and 6 months) and in APP/PS1 mice (at 4 and 10 months) (i) GFAP coverage, cell density, and complexity in hippocampus (HPC) and entorhinal cortex (EC); (ii) hippocampal gene expression of astrocyte markers; and (iii) the relationship between astrocyte, microglia, and amyloid markers.

In WT mice, ES increased GFAP coverage in HPC subregions at P9 and decreased it at 10 months. APP/PS1 mice at 10 months exhibited both individual cell as well as clustered GFAP signals. APP/PS1 mice when compared to WT exhibited reduced total GFAP coverage in HPC, which is increased in the EC, while coverage of the clustered GFAP signal in the HPC was increased and accompanied by increased expression of several astrocytic genes. While measured astrocytic parameters in APP/PS1 mice appear not be further modulated by ES, analyzing these in the context of ES-induced alterations to amyloid pathology and microglial shows alterations at both 4 and 10 months of age.

Our data suggest that ES leads to alterations to the astrocytic response to amyloid-β pathology.

• APP/PS1
• Astrocytes
• Aβ pathology
• Early stress
• GFAP
• Glia

• Gut microbiota
• Intestinal permeability
• Prebiotics
• Probiotics

Early‐life adversity (ELA) in the form of stress, inflammation, or malnutrition, can increase the risk of developing psychopathology or cognitive problems in adulthood. The neurobiological substrates underlying this process remain unclear. While neuronal dysfunction and microglial contribution have been studied in this context, only recently the role of astrocytes in early‐life programming of the brain has been appreciated. Astrocytes serve many basic roles for brain functioning (e.g., synaptogenesis, glutamate recycling), and are unique in their capacity of sensing and integrating environmental signals, as they are the first cells to encounter signals from the blood, including hormonal changes (e.g., glucocorticoids), immune signals, and nutritional information. Integration of these signals is especially important during early development, and therefore we propose that astrocytes contribute to ELA induced changes in the brain by sensing and integrating environmental signals and by modulating neuronal development and function. Studies in rodents have already shown that ELA can impact astrocytes on the short and long term, however, a critical review of these results is currently lacking. Here, we will discuss the developmental trajectory of astrocytes, their ability to integrate stress, immune, and nutritional signals from the early environment, and we will review how different types of early adversity impact astrocytes.

• GFAP
• early inflammation
• early malnutrition
• early stress
• maternal separation/deprivation

• Analgesics
• Chronic pain
• Clavulanic acid
• Excitotoxicity
• Glutamate transporters
• Glutamosome
• Intracellular signaling
• Scaffolding proteins

• Amino Acid Transport System X-AG/genetics
• Animals
• Biological Transport
• Chronic Pain/drug therapy
• Chronic Pain/genetics
• Chronic Pain/pathology
• Glutamates/genetics
• Glutamates/metabolism
• Humans
• Nociception/drug effects
• Nociception/physiology
• Pathology, Molecular
• Spinal Cord/drug effects
• Vesicular Glutamate Transport Proteins/antagonists & inhibitors
• Vesicular Glutamate Transport Proteins/biosynthesis
• Vesicular Glutamate Transport Proteins/genetics

A complex bidirectional communication system exists between the gastrointestinal tract and the brain. Initially termed the “gut-brain axis” it is now renamed the “microbiota-gut-brain axis” considering the pivotal role of gut microbiota in maintaining local and systemic homeostasis. Different cellular and molecular pathways act along this axis and strong attention is paid to neuroactive molecules (neurotransmitters, i.e., noradrenaline, dopamine, serotonin, gamma aminobutyric acid and glutamate and metabolites, i.e., tryptophan metabolites), sustaining a possible interkingdom communication system between eukaryota and prokaryota. This review provides a description of the most up-to-date evidence on glutamate as a neurotransmitter/neuromodulator in this bidirectional communication axis. Modulation of glutamatergic receptor activity along the microbiota-gut-brain axis may influence gut (i.e., taste, visceral sensitivity and motility) and brain functions (stress response, mood and behavior) and alterations of glutamatergic transmission may participate to the pathogenesis of local and brain disorders. In this latter context, we will focus on two major gut disorders, such as irritable bowel syndrome and inflammatory bowel disease, both characterized by psychiatric co-morbidity. Research in this area opens the possibility to target glutamatergic neurotransmission, either pharmacologically or by the use of probiotics producing neuroactive molecules, as a therapeutic approach for the treatment of gastrointestinal and related psychiatric disorders.

• dysbiosis
• glutamate
• glutamate receptors
• inflammatory bowel disease (IBD)
• irritable bowel syndrome (IBS)
• microbiota-gut-brain axis

• Animals
• Colon/drug effects
• Colon/metabolism
• Enzyme Activation/drug effects
• Female
• Guanylate Cyclase/metabolism
• Peptides/pharmacology
• Permeability/drug effects
• Rats
• Rats, Sprague-Dawley
• Signal Transduction/drug effects
• Spinal Cord/cytology
• Spinal Cord/drug effects
• Urinary Bladder/drug effects
• Urinary Bladder/metabolism

• IK6 BX003610 BLRD VA

Early life stress (ELS) leads to a permanent reprogramming of biochemical stress response cascades that may also be relevant for the processing of chronic pain states such as neuropathy. Despite clinical evidence, little is known about ELS-related vulnerability for neuropathic pain and the possibly underlying etiology.

In the framework of experimental studies aimed at investigating the respective relationships we used the established ELS model of maternal separation (MS). Rat dams and neonates were separated for 3 h/day from post-natal day 2–12. At adulthood, noxious mechanical and thermal thresholds were assessed before and during induction of neuropathic pain by chronic constriction injury (CCI). The potential involvement of spinal glutamatergic transmission, glial cells, pro-inflammatory cytokines and growth factors was studied by using qPCR.

MS per se did not modify pain thresholds. But, when exposed to neuropathic pain, MS rats exhibited a marked reduction of thermal sensitivity and a delayed development of mechanical allodynia/hyperalgesia when compared to control animals. Also, MS did not alter glucocorticoid receptor mRNA levels, but prevented the CCI-induced down-regulation of NR1 and NR2 sub-units of the NMDA receptor and of the glutamate transporter EAAT3 as observed at 21 days post-surgery. Additionally, CCI-provoked up-regulation of glial cell markers was either prevented (GFAP for astrocytes) or dampened (Iba1 for microglia) by MS. Pro-inflammatory cytokine mRNA expression was either not affected (IL-6) or reduced (IL-1β) by MS shortly after CCI. The growth factors GDNF and NGF were only slightly downregulated 4 days after CCI in the MS-treated animals. The changes in glutamatergic signaling, astroglial and cytokine activation as well as neurotrophin expression could, to some extent, explain these changes in pain behavior. Taken together, the results obtained in the described experimental conditions support the mismatch theory of chronic stress where an early life stress, rather than predisposing individuals to certain pathologies, renders them resilient.

• Early life stress
• Maternal separation
• Neuropathic pain
• Nociceptive transmission
• Spinal mediators

• Atosiban (PubChem CID: 5311010)
• Enteric glial cells
• Oxytocin
• Oxytocin (PubChem CID: 439302)
• TLR4/MyD88/NF-κB signaling
• Visceral hypersensitivity

To establish a rat model of anxiety-like gastric hypersensitivity (GHS) of functional dyspepsia (FD) induced by novel sequential stress.

Animal pups were divided into two groups from postnatal day 2: controls and the sequential-stress-treated. The sequential-stress-treated group received maternal separation and acute gastric irritation early in life and restraint stress in adulthood; controls were reared undisturbed with their mothers. Rats in both groups were followed to adulthood (8 wk) at which point the anxiety-like behaviors and visceromotor responses to gastric distention (20-100 mmHg) and gastric emptying were tested. Meanwhile, alterations in several anxiety-related brain-stomach modulators including 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), brain-derived neurotrophic factor (BDNF) and nesfatin-1 in the rat hippocampus, plasma and gastric fundus and the 5-HT1A receptor (5-HT1AR) in the hippocampal CA1 subfield and the mucosa of the gastric fundus were examined.

Sequential-stress-treated rats simultaneously demonstrated anxiety-like behaviors and GHS in dose-dependent manner compared with the control group. Although rats in both groups consumed similar amount of solid food, the rate of gastric emptying was lower in the sequential-stress-treated rats than in the control group. Sequential stress significantly decreased the levels of 5-HT (51.91 ± 1.88 vs 104.21 ± 2.88, P < 0.01), GABA (2.38 ± 0.16 vs 5.01 ± 0.13, P < 0.01) and BDNF (304.40 ± 10.16 vs 698.17 ± 27.91, P < 0.01) in the hippocampus but increased the content of nesfatin-1 (1961.38 ± 56.89 vs 1007.50 ± 33.05, P < 0.01) in the same site; significantly decreased the levels of 5-HT (47.82 ± 2.29 vs 89.45 ± 2.61, P < 0.01) and BDNF (257.05 ± 12.89 vs 536.71 ± 20.73, P < 0.01) in the plasma but increased the content of nesfatin-1 in it (1391.75 ± 42.77 vs 737.88 ± 33.15, P < 0.01); significantly decreased the levels of 5-HT (41.15 ± 1.81 vs 89.17 ± 2.31, P < 0.01) and BDNF (226.49 ± 12.10 vs 551.36 ± 16.47, P < 0.01) in the gastric fundus but increased the content of nesfatin-1 in the same site (1534.75 ± 38.52 vs 819.63 ± 38.04, P < 0.01). The expressions of 5-HT1AR in the hippocampal CA1 subfield and the mucosa of the gastric fundus were down-regulated measured by IHC (Optical Density value: Hippocampus 15253.50 ± 760.35 vs 21149.75 ± 834.13; gastric fundus 15865.25 ± 521.24 vs 23865.75 ± 1868.60; P < 0.05, respectively) and WB (0.38 ± 0.01 vs 0.57 ± 0.03, P < 0.01) (n = 8 in each group).

Sequential stress could induce a potential rat model of anxiety-like GHS of FD, which could be used to research the mechanisms of this intractable disease.

• Gastric hypersensitivity
• Anxiety
• Functional dyspepsia
• 5-hydroxytryptamine
• γ-aminobutyric acid
• Brain-derived neurotrophic factor
• Nesfatin-1
• Rat model

• Animals
• Anxiety/complications
• Disease Models, Animal
• Dyspepsia/blood
• Dyspepsia/etiology
• Dyspepsia/psychology
• Male
• Maternal Deprivation
• Rats, Sprague-Dawley
• Stress, Psychological/complications

• Brain-gut-microbiota axis
• Depression
• Early life stress
• Irritable bowel syndrome
• Psychiatric disease

The perception of visceral pain is a complex process involving the spinal cord and higher order brain structures. Increasing evidence implicates the gut microbiota as a key regulator of brain and behavior, yet it remains to be determined if gut bacteria play a role in visceral sensitivity. We used germ-free mice (GF) to assess visceral sensitivity, spinal cord gene expression and pain-related brain structures. GF mice displayed visceral hypersensitivity accompanied by increases in Toll-like receptor and cytokine gene expression in the spinal cord, which were normalized by postnatal colonization with microbiota from conventionally colonized (CC). In GF mice, the volumes of the anterior cingulate cortex (ACC) and periaqueductal grey, areas involved in pain processing, were decreased and enlarged, respectively, and dendritic changes in the ACC were evident. These findings indicate that the gut microbiota is required for the normal visceral pain sensation.

DOI:http://dx.doi.org/10.7554/eLife.25887.001

The human gut is home to over 100 trillion microbes collectively known as the gut microbiota. These microbes help us to digest food and absorb the nutrients effectively. A diverse and stable community of gut microbes is believed to be important for good health. Recently, it has also become clear that the microbiota can also influence the brain and how we behave. For example, many studies suggest that gut microbiota can alter how an individual perceives pain, but it is not clear how this works.

Rodents are often used in experiments as models of human biology. One of the most frequently used rodent models in studies of gut microbes is the “germ-free” mouse. These mice grow up in laboratory environments that are completely free of microbes, making it possible to study how having no gut microbes affects the health and behaviour of the mice. Luczynski, Tramullas et al. used germ-free mice to study how the gut microbiota influences an animal’s sensitivity to pain.

The experiments show that, compared to mice with normal gut microbiota, the germ-free mice were more sensitive to pain from internal organs especially the gut. These mice also produced larger amounts of specific proteins involved in immune responses, which contributed to the animal’s increased sensitivity to pain. Allowing the germ-free mice to be colonised with gut microbes could reverse these changes.

The experiments also show that the germ-free mice had changes in the size of two areas of the brain involved in sensing pain: an area called the anterior cingulate cortex was smaller, while the periaqueductal grey region was enlarged. There were also differences in individual nerve cells within the anterior cingulate cortex compared to normal mice.

The findings of Luczynski, Tramullas et al. reinforce the idea that the gut microbiota is involved in the sensation of pain from internal organs, and show that hypersensitivity to this form of pain can be reversed later in life by colonising the gut with microbes. Continuing to study the impact of microbes on this type of pain could aid the development of new therapies for the treatment of pain disorders in humans.

DOI:http://dx.doi.org/10.7554/eLife.25887.002

• Irritable Bowel Syndrome
• infectious disease
• microbiology
• microbiome
• microbiota-gut-brain axis
• mouse
• neuroscience
• periaqueductal gray
• stress
• toll-like receptor

• biochemical pathways
• cold sensitivity
• mechanical sensitivity
• neuropathy
• social stress

• dorsal root ganglion
• patch clamp recording
• posttraumatic stress disorder
• purinergic P2X3
• visceral hyperalgesia

• Amino acid transporter
• Ceftriaxone
• Clavulanic acid
• EAAT
• Gene transfer
• Glutamate
• Opioid tolerance
• Pain
• Riluzole
• Tricyclic antidepressant
• β-lactam antibiotic

• amygdala
• irritable bowel syndrome
• maternal separation
• nesfatin-1
• visceral hypersensitivity

• Brain-gut axis
• Enteric nervous system
• Excitotoxicity
• Gastrointestinal tract
• Glutamate

• Colorectal distension
• experimental colitis
• maternal separation
• stress

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.

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.

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.

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.

• Aspartate uptake
• Colorectal distension
• Early-life stress
• Excitatory amino acid transporter
• Glutamatergic system
• Visceral pain

Exposure to high-fat diet induces both, peripheral and central alterations in TLR4 expression. Moreover, functional TLR4 is required for the development of high-fat diet-induced obesity. Recently, central alterations in TLR4 expression have been associated with the modulation of visceral pain. However, it remains unknown whether there is a functional interaction between the role of TLR4 in diet-induced obesity and in visceral pain. In the present study we investigated the impact of long-term exposure to high-fat diet on visceral pain perception and on the levels of TLR4 and Cd11b (a microglial cell marker) protein expression in the prefrontal cortex (PFC) and hippocampus. Peripheral alterations in TLR4 were assessed following the stimulation of spleenocytes with the TLR4-agonist LPS. Finally, we evaluated the effect of blocking TLR4 on visceral nociception, by administering TAK-242, a selective TLR4-antagonist. Our results demonstrated that exposure to high-fat diet induced visceral hypersensitivity. In parallel, enhanced TLR4 expression and microglia activation were found in brain areas related to visceral pain, the PFC and the hippocampus. Likewise, peripheral TLR4 activity was increased following long-term exposure to high-fat diet, resulting in an increased level of pro-inflammatory cytokines. Finally, TLR4 blockage counteracted the hyperalgesic phenotype present in mice fed on high-fat diet. Our data reveal a role for TLR4 in visceral pain modulation in a model of diet-induced obesity, and point to TLR4 as a potential therapeutic target for the development of drugs to treat visceral hypersensitivity present in pathologies associated to fat diet consumption.

• Animals
• Brain/physiopathology
• Diet, High-Fat
• Male
• Mice
• Mice, Inbred C57BL
• Obesity/physiopathology
• Toll-Like Receptor 4/physiology
• Visceral Pain/physiopathology

• Science Foundation Ireland
• Health Research Board of Ireland
• European Community’s Seventh Framework Programme Grant My New Gut

• anandamide
• cannabinoid
• depression
• pain
• stress

• Addiction
• Glutamate
• Stress

• functional gastrointestinal disorders
• glial cells
• irritable bowel syndrome
• maternal separation
• stress

• IBS
• gastrointestinal
• models
• pain
• rodent

AIM: To explore the effect of neonatal maternal separation on the concentration of serum nesfatin-1 in rats.

METHODS: Newborn male Sprague-Dawley rats were randomly divided into either a maternal separation group or a control group. Rats in the maternal separation group received maternal separation from postnatal days 2-15. At the 8^th postnatal week, the abdominal withdrawal reflex (AWR) and electromyographic (EMG) amplitude of the external oblique muscle in response to graded colorectal distension (CRD) were examined. The levels of serum nesfatin-1 and glucocorticoid were detected using ELISA.

RESULTS: At the 8^th postnatal week, the body weight of rats in the maternal separation group was significantly lower than that in the normal control group. The levels of serum nesfatin-1 and glucocorticoid in maternal separation group were statistically higher than those in the control group. The level of glucocorticoid was positively correlated with serum nesfatin-1 level. When the balloon pressure was set at 40, 60 and 80 mmHg, AWR score and EMG amplitude in the maternal separation group were significantly higher than those in the normal control group. AWR score and EMG amplitude in the maternal separation group were positively correlated with the level of serum nesfatin-1.

CONCLUSION: Rats subjected to maternal separation showed a higher AWR score and EMG amplitude, as well as elevated levels of serum nesfatin-1. Visceral hypersensitivity induced by neonatal maternal separation may be associated with elevated level of serum nesfatin-1.

• Irritable bowel syndrome
• Visceral hypersensitivity
• Maternal separation
• Nesfatin-1

• BDNF
• animal behaviour
• anxiety
• colorectal distension
• depression
• glutamate
• mouse strain
• serotonin
• stress
• visceral pain

• Glutamate
• Pain
• Transporters

• animal models
• colorectal distension
• irritable-bowel syndrome
• microbiota–gut–brain axis
• psychological
• stress
• visceral pain

• early life stress
• pain
• rat

Pain in infancy influences pain reactivity in later life, but how and why this occurs is poorly understood. Here we review the evidence for developmental plasticity of nociceptive pathways in animal models and discuss the peripheral and central mechanisms that underlie this plasticity. Adults who have experienced neonatal injury display increased pain and injury-induced hyperalgesia in the affected region but mild injury can also induce widespread baseline hyposensitivity across the rest of the body surface, suggesting the involvement of several underlying mechanisms, depending upon the type of early life experience. Peripheral nerve sprouting and dorsal horn central sensitization, disinhibition and neuroimmune priming are discussed in relation to the increased pain and hyperalgesia, while altered descending pain control systems driven, in part, by changes in the stress/HPA axis are discussed in relation to the widespread hypoalgesia. Finally, it is proposed that the endocannabinoid system deserves further attention in the search for mechanisms underlying injury-induced changes in pain processing in infants and children.

• cannabinoids
• descending pain control
• experience dependent-plasticity
• hyperalgesia
• newborn infant

• Glutamate transporter
• Irritable bowel syndrome
• Riluzole
• Visceral pain