Visceral Sensation Research Articles

Oxytocin antagonist induced visceral pain and corticotropin-releasing hormone neuronal activation in the central nucleus of the amygdala during colorectal distention in mice

Activation of neurons containing oxytocin and corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) of the hypothalamus, the anterior cingulate cortex (ACC), and the central nucleus of the amygdala (CeA) during colorectal distention (CRD) is likely to play a crucial role in animal models of irritable bowel syndrome (IBS). Earlier studies in rodents showed that the microbiome is involved in social behavior via oxytocin expression in the brain. However, the detailed mechanism of visceral sensation and oxytocin is largely unknown. We tested the following hypotheses: (1) that oxytocin neurons in the PVN are activated by CRD, and (2) that the activation of oxytocin neurons by CRD is related to anxiety-like behavior, visceral perception, and an activation of CRH CeA neurons or ACC neurons. Oxytocin antagonist caused visceral hypersensitivity and anxiety-like behavior. In the PVN, oxytocin neurons were activated by CRD. Noxious CRD activated the CeA, basolateral nucleus of the amygdala (BLA), and ACC. High-dose oxytocin antagonist suppressed ACC activity and activated CRH CeA neurons. These results support our hypotheses. Oxytocin likely regulates CRH CeA neurons in an inhibitory manner and the ACC in an excitatory manner. Further research into the interaction of oxytocin and CRH in visceral pain and anxiety is warranted.

How Processing of Sensory Information From the Internal and External Worlds Shape the Perception and Engagement With the World in the Aftermath of Trauma: Implications for PTSD.

Post-traumatic stress disorder (PTSD) is triggered by an individual experiencing or witnessing a traumatic event, often precipitating persistent flashbacks and severe anxiety that are associated with a fearful and hypervigilant presentation. Approximately 14–30% of traumatized individuals present with the dissociative subtype of PTSD, which is often associated with repeated or childhood trauma. This presentation includes symptoms of depersonalization and derealization, where individuals may feel as if the world or self is “dream-like” and not real and/or describe “out-of-body” experiences. Here, we review putative neural alterations that may underlie how sensations are experienced among traumatized individuals with PTSD and its dissociative subtype, including those from the outside world (e.g., touch, auditory, and visual sensations) and the internal world of the body (e.g., visceral sensations, physical sensations associated with feeling states). We postulate that alterations in the neural pathways important for the processing of sensations originating in the outer and inner worlds may have cascading effects on the performance of higher-order cognitive functions, including emotion regulation, social cognition, and goal-oriented action, thereby shaping the perception of and engagement with the world. Finally, we introduce a theoretical neurobiological framework to account for altered sensory processing among traumatized individuals with and without the dissociative subtype of PTSD.

The effects of vibrotactile masking on heartbeat detection: Evidence that somatosensory mechanoreceptors transduce heartbeat sensations.

The ability to detect heartbeat sensations is the most common basis for inferring individual differences in sensitivity to the interoceptive stimuli generated by the visceral activity. While the sensory sources of heartbeat sensations have yet to be identified, there is a growing consensus that visceral sensation, in general, is supported not only by the interoceptive system but also by the somatosensory system, and even by exteroception. The current experiment sought evidence on this issue by exploring the effects of masking the functions of somatosensory Pacinian and non-Pacinian mechanoreceptors on the ability to detect heartbeat sensations. Twelve verified heartbeat detectors completed a multi-session experiment in which they judged heartbeat-tone and light-tone simultaneity under two vibrotactile masking conditions involving the stimulation of the sternum: (a) using 250Hz vibrotactile stimuli to mask the Pacinian channel, and (b) using 6Hz vibrotactile stimuli to mask the non-Pacinian channel. A no-vibration control condition in which no masking stimuli were presented was also implemented. Presentation of both the 250Hz and the 6Hz masking stimuli impaired the ability to judge the simultaneity of heartbeats and tones but did not influence the ability to judge the simultaneity of stimuli presented to different exteroceptive modalities (lights and tones). Our findings reinforce the view that the somatosensory system is involved in cardioception and support the conclusion that both Pacinian and non-Pacinian somatosensory mechanoreceptors are implicated in heartbeat detection.

Alterations of White Matter Network Properties in Patients With Functional Constipation.

Background: The abnormalities in brain function and structure of patients with functional constipation (FC) have been identified using multiple neuroimaging studies and have confirmed the abnormal processing of visceral sensation at the level of the central nervous system (CNS) as an important reason for FC. As an important basis for central information transfer, the role of the white matter (WM) networks in the pathophysiology of FC has not been investigated. This study aimed to explore the topological organization of WM networks in patients with FC and its correlation with clinical variables.Methods and Analysis: In this study, 70 patients with FC and 45 age- and gender-matched healthy subjects (HS) were recruited. Diffusion tensor imaging (DTI) data and clinical variables were acquired from each participant. WM networks were constructed using the deterministic fiber tracking approach, and the global and nodal properties of the WM networks were compared using graph theory analysis between patients with FC and HS. The relationship between the representative nodal characteristics–nodal betweenness and clinical parameters was assessed using partial correlation analysis.Results: Patients with FC showed increased nodal characteristics in the left superior frontal gyrus (orbital part), right middle frontal gyrus (orbital part), and right anterior cingulate and paracingulate (P < 0.05, corrected for false discovery rate) and decreased nodal characteristics in the left caudate and left thalamus (P < 0.05, corrected for false discovery rate) compared with HS. The duration of FC was negatively correlated with the nodal betweenness of the left thalamus (r = −0.354, P = 0.04, corrected for false discovery rate).Conclusion: The results indicated the alternations in WM networks of patients with FC and suggested the abnormal visceral sensation processing in the CNS from the perspective of large-scale brain WM network.

Abdominothoracic Postural Tone Influences the Sensations Induced by Meal Ingestion.

Postprandial objective abdominal distention is frequently associated with a subjective sensation of abdominal bloating, but the relation between both complaints is unknown. While the bloating sensation has a visceral origin, abdominal distention is a behavioral somatic response, involving contraction and descent of the diaphragm with protrusion of the anterior abdominal wall. Our aim was to determine whether abdominal distention influences digestive sensations. In 16 healthy women we investigated the effect of intentional abdominal distention on experimentally induced bloating sensation (by a meal overload). Participants were first taught to produce diaphragmatic contraction and visible abdominal distention. After a meal overload, sensations of bloating (0 to 10) and digestive well-being (−5 to + 5) were measured during 30-s. maneuvers alternating diaphragmatic contraction and diaphragmatic relaxation. Compared to diaphragmatic relaxation, diaphragmatic contraction was associated with diaphragmatic descent (by 21 + 3 mm; p < 0.001), objective abdominal distension (32 + 5 mm girth increase; p = 0.001), more intense sensation of bloating (7.3 + 0.4 vs. 8.0 + 0.4 score; p = 0.010) and lower digestive well-being (−0.9 + 0.5 vs. −1.9 + 0.5 score; p = 0.028). These results indicate that somatic postural tone underlying abdominal distention worsens the perception of visceral sensations (ClinicalTrials.gov ID: NCT04691882).

Berberine alleviates visceral hypersensitivity in rats by altering gut microbiome and suppressing spinal microglial activation

Accumulating evidence shows that agents targeting gut dysbiosis are effective for improving symptoms of irritable bowel syndrome (IBS). However, the potential mechanisms remain unclear. In this study we investigated the effects of berberine on the microbiota-gut-brain axis in two rat models of visceral hypersensitivity, i.e., specific pathogen-free SD rats subjected to chronic water avoidance stress (WAS) and treated with berberine (200 mg· kg−1 ·d−1, ig, for 10 days) as well as germ-free (GF) rats subjected to fecal microbiota transplantation (FMT) from a patient with IBS (designated IBS-FMT) and treated with berberine (200 mg· kg−1 ·d−1, ig, for 2 weeks). Before the rats were sacrificed, visceral sensation and depressive behaviors were evaluated. Then colonic tryptase was measured and microglial activation in the dorsal lumbar spinal cord was assessed. The fecal microbiota was profiled using 16S rRNA sequencing, and short chain fatty acids (SCFAs) were measured. We showed that berberine treatment significantly alleviated chronic WAS-induced visceral hypersensitivity and activation of colonic mast cells and microglia in the dorsal lumbar spinal cord. Transfer of fecal samples from berberine-treated stressed donors to GF rats protected against acute WAS. FMT from a patient with IBS induced visceral hypersensitivity and pro-inflammatory phenotype in microglia, while berberine treatment reversed the microglial activation and altered microbial composition and function and SCFA profiles in stools of IBS-FMT rats. We demonstrated that berberine did not directly influence LPS-induced microglial activation in vitro. In both models, several SCFA-producing genera were enriched by berberine treatment, and positively correlated to the morphological parameters of microglia. In conclusion, activation of microglia in the dorsal lumbar spinal cord was involved in the pathogenesis of IBS caused by dysregulation of the microbiota–gut–brain axis, and the berberine-altered gut microbiome mediated the modulatory effects of the agent on microglial activation and visceral hypersensitivity, providing a potential option for the treatment of IBS.

Efficacy of opioid receptor modulators in patients with irritable bowel syndrome: A systematic review and meta-analysis.

Background:While irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal diseases in clinical practice, it has diverse pathogenesis. Because of its sudden and lingering intractable symptoms, it seriously affects patients work and life. Opioid receptors are G protein-coupled receptors distributed across the brain, spinal cord, skin, and gastrointestinal tract, and each of the subtypes has a unique role and specific distribution. They play a role in regulating gastrointestinal motility, secretion, and visceral sensations in the gastrointestinal tract. Therefore, this meta-analysis aims to evaluate the effects of opioid receptor modulators on improving the symptoms of IBS.Methods:Searching the key words (Irritable Bowel Syndromes or Syndrome, Irritable Bowel OR Syndromes, Irritable Bowel OR Colon, Irritable OR Irritable Colon OR Colitis, Mucous OR Colitides, Mucous OR Mucous Colitides OR Mucous Colitis) AND (opioid receptor modulators OR eluxadoline OR Viberzi OR asimadoline OR loperamide), a preliminary search on PubMed (English), EMBASE (English), Cochrane Library (English), China National Knowledge Infrastructure Database (CNKI, Chinese), WanFang (Chinese), VIP citation databases (Chinese) and SinoMed (Chinese) databases yielded 1023 papers published in English and Chinese from inception to July 1, 2019. Nine studies were included in the final meta-analysis. Because this is a systematic review and meta-analysis, ethical approval is not necessary.Results:The random-effects meta-analysis based on these 9 studies and their 4156 patients found that opioid receptor modulators have a statistically significant beneficial effect on IBS global symptoms (RR = 0.85, 95%CI = 0.79–0.92, P < .01) and bowel movement frequency (SMD = −1.26, 95%CI = −2.49–−0.04, P < .05), and while there was an improvement trend in stool consistency and quality of life, these findings were not statistically significant.Conclusions:This is the first meta-analysis to examine the use of opioid receptor modulators in IBS, and few adverse events were reported in the available trials. Compared with the control group, eluxadolin has a better effect in improving IBS global symptoms and abdominal pain and has statistical significance and showed a low rate of constipation development in IBS patients in comparison with known effects of other opioid receptor modulators. However, current findings are based on a considerably limited evidence base with marked heterogeneity. Future studies should aim to identify subpopulations of patients with IBS and need to evaluate the long-term safety of these therapies.PROSPERO registration number: CRD42020141597.

The Prevalence of Enteropathy Symptoms from the Lower Gastrointestinal Tract and the Evaluation of Anorectal Function in Diabetes Mellitus Patients.

Complications affecting the gastrointestinal tract often occur in the course of diabetes mellitus (DM). The aim of this study was to evaluate enteropathy symptoms and anorectal function using high-resolution anorectal manometry (HRAM). Fifty DM patients and 20 non-DM controls were enrolled into the study. Clinical data and laboratory tests were collected, physical examination and HRAM were performed. Symptoms in the lower gastrointestinal tract were reported by 72% of patients. DM patients with a long disease duration reported anal region discomfort (p = 0.028) and a sensation of incomplete evacuation (p = 0.036) more often than patients with shorter diabetes duration. Overall, DM patients had a lower maximal squeeze pressure (MSP) (p = 0.001) and a higher mean threshold of minimal rectal sensation (p < 0.01) than control subjects. They presented with enhanced features of dyssynergic defection than the control group. MSP and maximal resting pressure (MRP) were significantly lower in the group of long-term diabetes (p = 0.024; p = 0.026 respectively) than in patients with a short-term diabetes. The same observation was noted for patients with enteropathy symptoms that control for MSP (p < 0.01; p < 0.01; p = 0.03) and MRP (p < 0.001; p = 0.0036; p = 0.0046), respectively, for incontinence, constipation, and diarrhea. Symptoms in the lower gastrointestinal tract are often reported by DM patients. All DM patients have impaired function of the external anal sphincter and present enhanced features of dyssynergic defecation and also impaired visceral sensation. Patients with long-standing DM and patients with enteropathy symptoms have severely impaired function of both anal sphincters.

Sensory profile alterations in patients with insular epilepsy surgery: Preliminary findings

The insular cortex is now well-established as a potential site of epileptogenesis in patients with drug-resistant epilepsy, and its resection has been associated with good outcomes in terms of seizure control. However, given the role of the insula in sensory processing and in visceral information integration, it remains unclear whether insular cortex epilepsy and its surgery are associated with disturbances in sensory information processing and visceral sensation processes as experienced in daily life. In the present study, we examined such sensory disturbances in a group of patients (n = 17) who underwent epilepsy surgery involving a resection of the insula and compared them to a lesion-control group of patients with temporal epilepsy surgery (n = 22) and a healthy control group (n = 29) matched for age, gender, and education. Participants were assessed on the self-report “Adolescent/Adult Sensory Profile” questionnaire at least four months after surgery. Our series of one-way analyses of variance (ANOVAs) revealed that insular and temporal resections in patients with drug-refractory epilepsy were associated with a low “sensation seeking” behavior reflecting a lack of engagement with sensory inputs from the environment. Furthermore, insular resections were associated with impairments in the “active behavioral responses” for the gustatory/olfactory modalities. These preliminary findings suggest that insular resections may be associated with mild to moderate alterations in sensory processing.

Remaking Romantic Love in Maria Edgeworth’s Belinda

ABSTRACT The emphasis on the unique self in the Romantic period resulted in representations of romantic love as an aspect of psychological depth. However, in Maria Edgeworth’s novel, Belinda (1901), love is represented as a function of visceral sensation and at best as automatic rather than reflective psychological processes. To some degree, Edgeworth was influenced by the scientific culture of her time in viewing love as a product of the external, observable world rather than of the interior mind. More surprisingly, perhaps, Edgeworth considers love as a function of high society, thus breaking down symptomatic associations of love and domesticity. In Belinda, love is a product of both the logical scientific method and the questionable morality characteristic of fashionable sociability. Standing partially outside the Romantic emphasis on psychological depth and the empirical insistence on rationality, Edgeworth theorises a love that questions the foundational concepts of subject/object and feeling/reason through which love has been understood from the Romantic era to the present day.

Embodiment in Active Sport Tourism: An Autophenomenography of the Tour de France Alpine “Cols”

Existing conceptualizations of active sport tourism lack an empirical foundation in explaining the processes of embodiment through which active sport tourists engage with destination space. Adopting an autophenomenographic perspective, this paper explores embodiment in the context of a cycling tourism experience encompassing six iconic mountain passes within the French Alps synonymous with the Tour de France. Qualitative data draw attention to kinaesthetic and visceral sensations arising through multisensory feedback, along with affective responses produced as the body traverses venerated sport landscapes. This research highlights mind–body processes that shape mobile, active sport tourism experiences and provides an empirical and conceptual foundation to inform future studies of embodiment in active sport tourism.

Supraspinal Mechanisms of Intestinal Hypersensitivity.

Gut inflammation or injury causes intestinal hypersensitivity (IHS) and hyperalgesia, which can persist after the initiating pathology resolves, are often referred to somatic regions and exacerbated by psychological stress, anxiety or depression, suggesting the involvement of both the spinal cord and the brain. The supraspinal mechanisms of IHS remain to be fully elucidated, however, over the last decades the series of intestinal pathology-associated neuroplastic changes in the brain has been revealed, being potentially responsible for the phenomenon. This paper reviews current clinical and experimental data, including the authors' own findings, on these functional, structural, and neurochemical/molecular changes within cortical, subcortical and brainstem regions processing and modulating sensory signals from the gut. As concluded in the review, IHS can develop and maintain due to the bowel inflammation/injury-induced persistent hyperexcitability of viscerosensory brainstem and thalamic nuclei and sensitization of hypothalamic, amygdala, hippocampal, anterior insular, and anterior cingulate cortical areas implicated in the neuroendocrine, emotional and cognitive modulation of visceral sensation and pain. An additional contribution may come from the pathology-triggered dysfunction of the brainstem structures inhibiting nociception. The mechanism underlying IHS-associated regional hyperexcitability is enhanced NMDA-, AMPA- and group I metabotropic receptor-mediated glutamatergic neurotransmission in association with altered neuropeptide Y, corticotropin-releasing factor, and cannabinoid 1 receptor signaling. These alterations are at least partially mediated by brain microglia and local production of cytokines, especially tumor necrosis factor α. Studying the IHS-related brain neuroplasticity in greater depth may enable the development of new therapeutic approaches against chronic abdominal pain in inflammatory bowel disease.

Imipramine improves visceral sensation and gut barrier in rat models of irritable bowel syndrome

An impaired gut barrier, possibly leading to visceral hypersensitivity has been recently recognized to be one of the pivotal pathophysiology of irritable bowel syndrome (IBS). We previously showed that lipopolysaccharide (LPS), corticotropin-releasing factor (CRF), and repeated water avoidance stress (WAS) induce visceral hypersensitivity and colonic hyperpermeability via pro-inflammatory cytokine signaling (rat IBS models). Although the precise mechanisms of action are unclear, imipramine, a tricyclic antidepressant, improves IBS symptoms, and also has anticytokine properties. In this study, we hypothesized that imipramine improves the gut barrier to ameliorate IBS symptoms. To test this hypothesis, we determined its effects on visceral hypersensitivity and colonic hyperpermeability in rat IBS models. The visceral pain threshold in response to colonic balloon distention was electrophysiologically estimated by abdominal muscle contractions, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue in vivo. Subcutaneous imipramine injection (7, 20, 50 mg/kg) dose-dependently inhibited LPS-induced (1 mg/kg, subcutaneously) visceral hypersensitivity and colonic hyperpermeability. Imipramine also blocked these gastrointestinal (GI) changes induced by CRF (50 μg/kg, intraperitoneally) or repeated WAS (1 h daily for 3 days). Yohimbine (an α2-adrenoceptors antagonist), sulpiride (a dopamine D2 receptor antagonist), and naloxone hydrochloride (an opioid receptor antagonist) reversed these effects of imipramine in the LPS model. Therefore, imipramine may block GI changes in IBS via α2-adrenoceptors, dopamine D2, and opioid signaling. The improvement in the gut barrier resulting in inhibition of visceral pain is considered a valid mechanism of imipramine to ameliorate IBS symptoms.

Duodenal chemosensory system: enterocytes, enteroendocrine cells, and tuft cells.

The gut barrier serves as the primary interface between the environment and host in terms of surface area and complexity. Luminal chemosensing is a term used to describe how small molecules in the gut lumen interact with the host through surface receptors or via transport into the subepithelial space. In this review, we have summarized recent advances in the understanding of the luminal chemosensory system in the gastroduodenal epithelium consisting of enterocytes, enteroendocrine, and tuft cells, with particular emphasis on how chemosensing affects mucosal protective responses and the metabolic syndrome. Recent single-cell RNA sequencing provides detailed cell type-specific expression of chemosensory receptors and other bioactive molecules as well as cell lineages; some are similar to lingual taste cells whereas some are gut specific. Gut luminal chemosensing is not only important for the local or remote regulation of gut function, but also contributes to the systemic regulation of metabolism, energy balance, and food intake. We will discuss the chemosensory mechanisms of the proximal intestine, in particular to gastric acid, with a focus on the cell types and receptors involved in chemosensing, with emphasis on the rare chemosensory cells termed tuft cells. We will also discuss the chemosensory functions of intestinal ectoenzymes and bacterial components (e.g., lipopolysaccharide) as well as how they affect mucosal function through altering the gut-hormonal-neural axis. Recent updates in luminal chemosensing by different chemosensory cells have provided new possibilities for identifying novel molecular targets for the treatment of mucosal injury, metabolic disorders, and abnormal visceral sensation.

Unique Molecular Characteristics of Visceral Afferents Arising from Different Levels of the Neuraxis: Location of Afferent Somata Predicts Function and Stimulus Detection Modalities.

Viscera receive innervation from sensory ganglia located adjacent to multiple levels of the brainstem and spinal cord. Here we examined whether molecular profiling could be used to identify functional clusters of colon afferents from thoracolumbar (TL), lumbosacral (LS), and nodose ganglia (NG) in male and female mice. Profiling of TL and LS bladder afferents was also performed. Visceral afferents were back-labeled using retrograde tracers injected into proximal and distal regions of colon or bladder, followed by single-cell qRT-PCR and analysis via an automated hierarchical clustering method. Genes were chosen for assay (32 for bladder; 48 for colon) based on their established role in stimulus detection, regulation of sensitivity/function, or neuroimmune interaction. A total of 132 colon afferents (from NG, TL, and LS ganglia) and 128 bladder afferents (from TL and LS ganglia) were analyzed. Retrograde labeling from the colon showed that NG and TL afferents innervate proximal and distal regions of the colon, whereas 98% of LS afferents only project to distal regions. There were clusters of colon and bladder afferents, defined by mRNA profiling, that localized to either TL or LS ganglia. Mixed TL/LS clustering also was found. In addition, transcriptionally, NG colon afferents were almost completely segregated from colon TL and LS neurons. Furthermore, colon and bladder afferents expressed genes at similar levels, although different gene combinations defined the clusters. These results indicate that genes implicated in both homeostatic regulation and conscious sensations are found at all anatomic levels, suggesting that afferents from different portions of the neuraxis have overlapping functions.SIGNIFICANCE STATEMENT Visceral organs are innervated by sensory neurons whose cell bodies are located in multiple ganglia associated with the brainstem and spinal cord. For the colon, this overlapping innervation is proposed to facilitate visceral sensation and homeostasis, where sensation and pain are mediated by spinal afferents and fear and anxiety (the affective aspects of visceral pain) are the domain of nodose afferents. The transcriptomic analysis performed here reveals that genes implicated in both homeostatic regulation and pain are found in afferents across all ganglia types, suggesting that conscious sensation and homeostatic regulation are the result of convergence, and not segregation, of sensory input.

Tenapanor: new approach to counter irritable bowel syndrome with constipation

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder chronic in nature and characterized predominantly by abdominal pain or discomfort associated with altered bowel habits, diagnosis requires characteristic symptoms during the last 3 months and onset ≥6 months ago. Symptom-based approaches for functional bloating, constipation and diarrhea are best utilised to identify IBS. IBS with constipation exerts significant impairment on work productivity by hampering quality of life. Inadequate relief by existing modalities, persistent hard stools and visceral abdominal pain demanded further clinical research. Tenanapor a novel molecule acts locally on gastrointestinal sodium/hydrogen exchanger isoform 3 (NHE3), an antiporter a counter transporter and exert antinociceptive effects on visceral sensation thereby decreases the frequency of abdominal pain. Action on NHE3 receptors located on small intestine and colon’s apical surface reduces the absorption of sodium and phosphate, with minimal systemic exposure. NHE3 Inhibition induced sodium absorption results in increase in water secretion into intestinal lumen resultant an accelerated intestinal transit time and softer stool consistency. Most common adverse reactions (≥2%) are diarrhea, abdominal distension, flatulence and dizziness. The drug is metabolised mainly by CYP3A4/5 and excreted in feaces (70%) and urine (7%). Tenapanor’s minimal systemic absorption is likely to be associated with a relatively inert safety and tolerability profile. Based on positive results from the phase III T3MPO trial program, tenapanor demonstrated promising results for IBS-C management and received US Food and Drug Administration approval as IBSRELA @ Ardelyx Pharma in September 2019 and augment existing modalities for management of IBS-C.

Central afferents to the nucleus of the solitary tract in rats and mice.

The nucleus of the solitary tract (NTS) regulates life-sustaining functions ranging from appetite and digestion to heart rate and breathing. It is also the brain's primary sensory nucleus for visceral sensations relevant to symptoms in medical and psychiatric disorders. To better understand which neurons may exert top-down control over the NTS, here we provide a brain-wide map of all neurons that project axons directly to the caudal, viscerosensory NTS, focusing on a medial subregion with aldosterone-sensitive HSD2 neurons. Injecting an axonal tracer (cholera toxin b) into the NTS produces a similar pattern of retrograde labeling in rats and mice. The paraventricular hypothalamic nucleus (PVH), lateral hypothalamic area, and central nucleus of the amygdala (CeA) contain the densest concentrations of NTS-projecting neurons. PVH afferents are glutamatergic (express Slc17a6/Vglut2) and are distinct from neuroendocrine PVH neurons. CeA afferents are GABAergic (express Slc32a1/Vgat) and are distributed largely in the medial CeA subdivision. Other retrogradely labeled neurons are located in a variety of brain regions, including the cerebral cortex (insular and infralimbic areas), bed nucleus of the stria terminalis, periaqueductal gray, Barrington's nucleus, Kölliker-Fuse nucleus, hindbrain reticular formation, and rostral NTS. Similar patterns of retrograde labeling result from tracer injections into different NTS subdivisions, with dual retrograde tracing revealing that many afferent neurons project axon collaterals to both the lateral and medial NTS subdivisions. This information provides a roadmap for studying descending axonal projections that may influence visceromotor systems and visceral "mind-body" symptoms.

Fear in the context of pain: Lessons learned from 100 years of fear conditioning research

Human fear conditioning research since Watson's case study on “Little Albert” has vastly evolved and its impact today is reaching far beyond phobic anxiety. This review focuses on how fear conditioning research, mainly using exteroceptive conditioned stimuli (CSs) and aversive, non-noxious stimuli as unconditioned stimuli (USs), has been extended and translated to chronic pain research. We describe the different pain-related fear conditioning paradigms using proprioceptive and interoceptive CSs and painful stimuli as USs that have been developed to study specific forms of pain-related fear (i.e. fear of movement, fear of touch, fear of visceral sensations, and fear of penetration) that are relevant for different chronic pain conditions (i.e. musculoskeletal pain, neuropathic pain, visceral pain, and genital pain). We present evidence that patients with chronic pain demonstrate impaired safety learning and excessive fear generalization; learning anomalies that have also been observed in anxiety disorders. Extinction-based protocols (exposure in vivo) have been developed to reduce pain-related fear and increase daily functioning in various chronic pain disorders. Finally, we outline some challenges and future directions to further our understanding of learning mechanisms underlying the development, persistence, and treatment of chronic pain disability.

Microbiota-neuroimmune cross talk in stress-induced visceral hypersensitivity of the bowel.

Visceral hypersensitivity of the lower gastrointestinal tract, defined as an increased response to colorectal distension, frequently prompts episodes of debilitating abdominal pain in irritable bowel syndrome (IBS). Although the pathophysiology of IBS is not yet fully elucidated, it is well known that stress is a major risk factor for development and acts as a trigger of pain sensation. Stress modulates both immune responses as well as the gut microbiota and vice versa. Additionally, either microbes themselves or through involvement of the immune system, activate or sensitize afferent nociceptors. In this paper, we review current knowledge on the influence of stress along the gut-brain-microbiota axis and exemplify relevant neuroimmune cross talk mechanisms in visceral hypersensitivity, working toward understanding how gut microbiota-neuroimmune cross talk contributes to visceral pain sensation in IBS patients.

Adenosine A1 receptor agonist induces visceral antinociception via 5-HT1A, 5-HT2A, dopamine D1 or cannabinoid CB1 receptors, and the opioid system in the central nervous system

We have recently demonstrated that N(6)-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, acts centrally to induce a visceral antinociception. Since serotonin (5-HT), cannabinoid (CB), dopamine or opioid signaling in the central nervous system is involved in the regulation of visceral sensation, we made a hypothesis that the signaling may play a role in the CPA-induced visceral antinociception. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously administered CPA significantly increased the threshold of colonic distension-induced AWR. Intracisternal injection of either 5-HT1A or 5-HT2A receptor antagonist blocked the CPA-induced visceral antinociception while 5-HT1B antagonist did not block the CPA-induced visceral antinociception. Subcutaneous injection of dopamine D1 receptor antagonist, CB1 receptor antagonist or naloxone significantly blocked the CPA-induced visceral antinociception while neither subcutaneous injection of dopamine D2 receptor antagonist nor CB2 receptor antagonist blocked the CPA-induced anti-pain action. These results suggest that 5-HT1A, 5-HT2A, dopamine D1, CB1 receptors and the opioid system in the CNS may specifically mediate the CPA-induced visceral antinociception. These findings may help in understanding the physiological relevance of central adenosine with special reference to the pathophysiology of altered visceral sensation especially in irritable bowel syndrome.