Visceral Stimulation Research Articles

Contributions of the Cerebellum to Disturbed Central Processing of Visceral Stimuli in Irritable Bowel Syndrome

There is evidence to support that the cerebellum contributes to the neural processing of both emotions and painful stimuli. This could be particularly relevant in conditions associated with chronic abdominal pain, such as the irritable bowel syndrome (IBS), which are often also characterized by affective disturbances. We aimed to test the hypothesis that in IBS, symptoms of anxiety and depression modulate brain activation during visceral stimulation within the cerebellum. We reanalyzed a previous data set from N = 15 female IBS patients and N = 12 healthy women with a specific focus on the cerebellum using advanced normalization methods. Rectal distension-induced brain activation was measured with functional magnetic resonance imaging using non-painful and painful rectal distensions. Symptoms of anxiety and depression, assessed with the Hospital Anxiety and Depression scale, were correlated with cerebellar activation within IBS patients. Within IBS, depression scores were associated with non-painful distension-induced activation in the right cerebellum primarily in Crus II and lobule VIIIb, and additionally in Crus I. Depression scores were also associated with painful distension-induced activation predominantly in vermal lobule V with some extension to the intermediate cerebellum. Anxiety scores correlated significantly with non-painful induced activation in Crus II. Symptoms of anxiety and depression, which are frequently found in chronic pain conditions like IBS, modulate activation during visceral sensory signals not only in cortical and subcortical brain areas but also in the cerebellum.

Altered Cognitive Function of Prefrontal Cortex During Error Feedback in Patients With Irritable Bowel Syndrome, Based on fMRI and Dynamic Causal Modeling

Patients with irritable bowel syndrome (IBS) have increased activity in the insula and reduced activation of the dorsolateral prefrontal cortex (DLPFC) in response to visceral stimulation. We investigated whether they have latent impairments in cognitive flexibility because of dysfunction in the DLPFC and insula and altered connectivity between brain regions. We analyzed data from 30 individuals with IBS (15 men; age, 21.7 ± 3.0 y) diagnosed based on Rome III criteria, along with 30 individuals matched for age, sex, and education level (controls). Event-related functional magnetic resonance imaging of the brain was performed to evaluate cognitive flexibility and was assessed by the Wisconsin Card Sorting Test, in which subjects are allowed to change choice criteria, defined as set-shifting in response to error feedback. Brain images were analyzed with statistical parametric mapping 5 and 8 software and dynamic causal modeling. Subjects with IBS had significantly more Nelson perseverative errors (P < .05) and set-maintenance difficulties (P < .05) than controls. They also showed significantly decreased activity of the right DLPFC (Brodmann's area 9; P < .001) and right hippocampus (P < .001), and significantly increased activity of the left posterior insula (P < .001) at error feedback during set-shifting. Dynamic causal modeling analysis during set-shifting revealed significantly less connectivity from the DLPFC to pre-supplementary motor area in subjects with IBS, compared with controls (P = .012). Individuals with IBS have latent impairments in cognitive flexibility as a result of altered activity of the DLPFC, insula, and hippocampus, and impaired connectivity between the DLPFC and pre-supplementary motor area.

Neuroplastic alterations in brain responses to painful visceral stimulations reflects individual neuropathic symptoms in diabetes mellitus patients

Abstract Background/aims Abnormal visceral sensory function in diabetes mellitus (DM) leads to neuronal changes in the enteric, peripheral and/or central nervous system (CNS). To explore the role of diabetic autonomic neuropathy (DAN) in patients with long-standing DM, we investigated psychophysical responses and neuronal activity recorded as evoked brain potentials (EPs) and dipolar source modelling. Methods Fifteen healthy volunteers and 14 type-1 DM patients with DAN were assessed with a symptom score index characterizing upper GI abnormalities. Multi-channel (62) electroencephalography was recorded during painful electrical stimulation of the lower oesophagus. Brain activity to painful stimulations was modelled by use of Brain Electrical Source Analysis (BESA). Results Diabetic patients had higher stimulus intensities to evoke painful sensation (P&lt;0.001), longer latencies of N2 and P2 components (both P&lt;0.001), lower amplitudes of P1–N2 and N2–P2 complexes (P&lt;0.001; P = 0.02). Inverse modelling of brain sources showed deeper bilateral insular dipolar source localization (P = 0.002). Symptom score index was negatively correlated to the depth of insular activity (P = 0.004) and positively correlated to insular dipole strength (P = 0.03). Conclusion DM patients show neuroplastic changes in the central nervous system. The role of abnormal insular processing may explain the development and persistence of upper GI-symptoms related to DAN. This enhanced understanding of DAN may have clinical and therapeutical implications.

Su1971 The Effects of Oxytocin on Gastric Motility are Mediated by Different Neuronal Pathways in an Iodoacetamide Model of Functional Dyspepsia

Background: Insula represents an important site in the brain for multi-modal convergence and has been implicated in processing of visceral sensation. Earlier fMRI studies in humans (Lawall, et al. Am J Physiol 2008;294:G787-94) have shown activation and sensitization of insula in response to esophageal acid stimulation. However, response characteristics of insular neurons to esophageal chemical and mechanical stimulation have not been studied. Aims: Our aims in this study were: (i) to determine the influence of esophageal acid stimulation on the insular cortex neurons (ICNs) and (ii) to characterize the responses of these neurons to esophageal distension (ED) and colorectal distension (CRD) before and after esophageal acid exposure. Methods: Eleven male rats (SD, 300-400g) were initially anaesthetized with a mixture of α-chloralose (80mg/kg, i.p.) + urethane (800mg/kg, i.p.). The anesthetics were periodically supplemented (i.v.) every 3 hours with one-fourth of the initial dose and the blood pressure was constantly monitored. A craniotomy (Bregma: +2.5 to -2.5 mm, 2.0 to 7.0 mm lateral) was performed to access insular cortex (IC). Extracellular recordings from the ICNs (Bregma: +1.8 to -2.2 mm, 5.0 to 7.4 mm lateral, 5.8 to 7.8 mm dorso-ventral) were made from the neurons that responded to ED (30-60 mmHg) and/or CRD (30-60 mmHg). After characterization of ICNs to visceral stimulation (ED and CRD), 0.1 ml of PBS (0.1M, pH 7.4) was infused slowly (0.1ml/min) into the esophagus followed by the same volume of 0.1N HCl (pH 1.2). The infusate (0.1 ml) was applied three times at 60s, 300s and 540s. The interval of each infusion time was 4 minutes. The ED and CRD were repeated 15 minutes after acid infusion to study the responses of neurons. Results: Fifteen ED or CRD sensitive neurons were studied for their responses to PBS and acid infusion. All neurons (15/15, 100%) exhibited excitation (p<0.05) following acid infusion, whereas PBS had no effect on the responses of these neurons. Eleven EDand 10 CRDresponsive neurons were fully characterized to preand post-acid condition. Following acid infusion, 11/11 (100%) ED-responsive neurons exhibited increased activity in response to ED. In contrast, 10/10 (100%) CRD-responsive neurons exhibited decreased activity during CRD. In addition, acid, but not PBS, infusion increased the spontaneous firing of all recorded neurons and continued for 30 to 45 minutes after cessation of infusion. Conclusions: Intraesophageal acid infusion significantly alters the response characteristics of ICNs in rats. Esophageal acid infusion differentially modulates the activities of ICNs that receive convergent input from esophagus and colon.

Su1970 Effects of Oxytocin on Gastric-Projecting Neurons in a Rat Model of Functional Dyspepsia

Background: Insula represents an important site in the brain for multi-modal convergence and has been implicated in processing of visceral sensation. Earlier fMRI studies in humans (Lawall, et al. Am J Physiol 2008;294:G787-94) have shown activation and sensitization of insula in response to esophageal acid stimulation. However, response characteristics of insular neurons to esophageal chemical and mechanical stimulation have not been studied. Aims: Our aims in this study were: (i) to determine the influence of esophageal acid stimulation on the insular cortex neurons (ICNs) and (ii) to characterize the responses of these neurons to esophageal distension (ED) and colorectal distension (CRD) before and after esophageal acid exposure. Methods: Eleven male rats (SD, 300-400g) were initially anaesthetized with a mixture of α-chloralose (80mg/kg, i.p.) + urethane (800mg/kg, i.p.). The anesthetics were periodically supplemented (i.v.) every 3 hours with one-fourth of the initial dose and the blood pressure was constantly monitored. A craniotomy (Bregma: +2.5 to -2.5 mm, 2.0 to 7.0 mm lateral) was performed to access insular cortex (IC). Extracellular recordings from the ICNs (Bregma: +1.8 to -2.2 mm, 5.0 to 7.4 mm lateral, 5.8 to 7.8 mm dorso-ventral) were made from the neurons that responded to ED (30-60 mmHg) and/or CRD (30-60 mmHg). After characterization of ICNs to visceral stimulation (ED and CRD), 0.1 ml of PBS (0.1M, pH 7.4) was infused slowly (0.1ml/min) into the esophagus followed by the same volume of 0.1N HCl (pH 1.2). The infusate (0.1 ml) was applied three times at 60s, 300s and 540s. The interval of each infusion time was 4 minutes. The ED and CRD were repeated 15 minutes after acid infusion to study the responses of neurons. Results: Fifteen ED or CRD sensitive neurons were studied for their responses to PBS and acid infusion. All neurons (15/15, 100%) exhibited excitation (p<0.05) following acid infusion, whereas PBS had no effect on the responses of these neurons. Eleven EDand 10 CRDresponsive neurons were fully characterized to preand post-acid condition. Following acid infusion, 11/11 (100%) ED-responsive neurons exhibited increased activity in response to ED. In contrast, 10/10 (100%) CRD-responsive neurons exhibited decreased activity during CRD. In addition, acid, but not PBS, infusion increased the spontaneous firing of all recorded neurons and continued for 30 to 45 minutes after cessation of infusion. Conclusions: Intraesophageal acid infusion significantly alters the response characteristics of ICNs in rats. Esophageal acid infusion differentially modulates the activities of ICNs that receive convergent input from esophagus and colon.

Su1972 Characterization of a Rodent Model for Functional MRI Studies of Esophageal Acid Related Sensory Physiology

Background: Insula represents an important site in the brain for multi-modal convergence and has been implicated in processing of visceral sensation. Earlier fMRI studies in humans (Lawall, et al. Am J Physiol 2008;294:G787-94) have shown activation and sensitization of insula in response to esophageal acid stimulation. However, response characteristics of insular neurons to esophageal chemical and mechanical stimulation have not been studied. Aims: Our aims in this study were: (i) to determine the influence of esophageal acid stimulation on the insular cortex neurons (ICNs) and (ii) to characterize the responses of these neurons to esophageal distension (ED) and colorectal distension (CRD) before and after esophageal acid exposure. Methods: Eleven male rats (SD, 300-400g) were initially anaesthetized with a mixture of α-chloralose (80mg/kg, i.p.) + urethane (800mg/kg, i.p.). The anesthetics were periodically supplemented (i.v.) every 3 hours with one-fourth of the initial dose and the blood pressure was constantly monitored. A craniotomy (Bregma: +2.5 to -2.5 mm, 2.0 to 7.0 mm lateral) was performed to access insular cortex (IC). Extracellular recordings from the ICNs (Bregma: +1.8 to -2.2 mm, 5.0 to 7.4 mm lateral, 5.8 to 7.8 mm dorso-ventral) were made from the neurons that responded to ED (30-60 mmHg) and/or CRD (30-60 mmHg). After characterization of ICNs to visceral stimulation (ED and CRD), 0.1 ml of PBS (0.1M, pH 7.4) was infused slowly (0.1ml/min) into the esophagus followed by the same volume of 0.1N HCl (pH 1.2). The infusate (0.1 ml) was applied three times at 60s, 300s and 540s. The interval of each infusion time was 4 minutes. The ED and CRD were repeated 15 minutes after acid infusion to study the responses of neurons. Results: Fifteen ED or CRD sensitive neurons were studied for their responses to PBS and acid infusion. All neurons (15/15, 100%) exhibited excitation (p<0.05) following acid infusion, whereas PBS had no effect on the responses of these neurons. Eleven EDand 10 CRDresponsive neurons were fully characterized to preand post-acid condition. Following acid infusion, 11/11 (100%) ED-responsive neurons exhibited increased activity in response to ED. In contrast, 10/10 (100%) CRD-responsive neurons exhibited decreased activity during CRD. In addition, acid, but not PBS, infusion increased the spontaneous firing of all recorded neurons and continued for 30 to 45 minutes after cessation of infusion. Conclusions: Intraesophageal acid infusion significantly alters the response characteristics of ICNs in rats. Esophageal acid infusion differentially modulates the activities of ICNs that receive convergent input from esophagus and colon.

Analysis of brain activity during visceral stimulation

Functional magnetic resonance imaging (fMRI) is a useful technology for investigating regional metabolic activity in the brain. Many experiments using fMRI have been performed, but because of variations in protocols and analytic techniques, the results vary. When a priori information of the task is known, a model-based technique, such as statistical parametric mapping, is often used for analysis. In the case of acid stimulation of the esophagus the task model is unclear, so we analyzed brain activity during an acid or isotonic saline infusion to the esophagus using independent component analysis (ICA), which does not depend on a priori information of the task. Six healthy male volunteers (29-45 years) participated in the study. A multi-lumen catheter was inserted transnasally and side-hole infusions ports were approximately 15 cm proximal to the lower esophageal sphincter. The experimental protocol was 5-min interval, 5-min saline infusion, 5-min interval, 5-min 0.1 N HCl, and a final 5-min interval. After magnetic resonance scanning, fMRI image data were analyzed using group ICA. The cerebral regions activated during the first interval, saline infusion, and HCl infusion were the thalamus, insula, cingulate gyri, temporal pole and some parts of the frontal, parietal, temporal and occipital lobes. Activation of the postcentral and precentral gyri occurred during both infusions, but was not observed during the first interval. ICA, which can show the cerebral areas activated in relation to liquid in the esophagus, may be a powerful technique for studying the brain's response to visceral stimulation.

Are all spinal segments equal: intrinsic membrane properties of superficial dorsal horn neurons in the developing and mature mouse spinal cord

Neurons in the superficial dorsal horn (SDH; laminae I-II) of the spinal cord process nociceptive information from skin, muscle, joints and viscera. Most of what we know about the intrinsic properties of SDH neurons comes from studies in lumbar segments of the cord even though clinical evidence suggests nociceptive signals from viscera and head and neck tissues are processed differently. This ‘lumbar-centric' view of spinal pain processing mechanisms also applies to developing SDH neurons. Here we ask whether the intrinsic membrane properties of SDH neurons differ across spinal cord segments in both the developing and mature spinal cord. Whole cell recordings were made from SDH neurons in slices of upper cervical (C2-4), thoracic (T8-10) and lumbar (L3-5) segments in neonatal (P0-5) and adult (P24-45) mice. Neuronal input resistance (R(IN)), resting membrane potential, AP amplitude, half-width and AHP amplitude were similar across spinal cord regions in both neonates and adults (∼100 neurons for each region and age). In contrast, these intrinsic membrane properties differed dramatically between neonates and adults. Five types of AP discharge were observed during depolarizing current injection. In neonates, single spiking dominated (∼40%) and the proportions of each discharge category did not differ across spinal regions. In adults, initial bursting dominated in each spinal region, but was significantly more prevalent in rostral segments (49% of neurons in C2-4 vs. 29% in L3-5). During development the dominant AP discharge pattern changed from single spiking to initial bursting. The rapid A-type potassium current (I(Ar)) dominated in neonates and adults, but its prevalence decreased (∼80% vs. ∼50% of neurons) in all regions during development. I(Ar) steady state inactivation and activation also changed in upper cervical and lumbar regions during development. Together, our data show the intrinsic properties of SDH neurons are generally conserved in the three spinal cord regions examined in both neonate and adult mice. We propose the conserved intrinsic membrane properties of SDH neurons along the length of the spinal cord cannot explain the marked differences in pain experienced in the limbs, viscera, and head and neck.

Is Constant Current or Constant Voltage Spinal Cord Stimulation Superior for the Suppression of Nociceptive Visceral and Somatic Stimuli? A Rat Model

This study compares the effects of constant current (CC) and constant voltage (CV) spinal cord stimulation (SCS) at various frequencies and intensities on standard nociceptive measurements in rats, the visceromotor reflex (VMR) and neuronal activity, during noxious visceral and somatic stimuli. Abdominal muscle electromyographic activity changes were measured to indicate VMR, and extracellular activity of L6-S2 spinal neurons was recorded during somatic (pinching) and noxious visceral stimulation (colorectal distension [CRD], 60 mmHg) in anesthetized rats. A stimulating (unipolar ball) electrode at L2-L3 delivered CC- or CV-SCS at varied frequencies and intensities. CC-SCS reduced VMR evoked by CRD significantly more than CV-SCS (p < 0.05). For neuronal activity, high-frequency CC-SCS (40 and 100 Hz) and CV-SCS (100 Hz) effectively reduced intraspinal somatic nociceptive transmission more than low-frequency SCS (2 Hz). No significant differences were observed between the effects of CC- and CV-SCS on spontaneous activity and nociceptive responses of spinal neurons to noxious CRD following short- (five to ten minutes) or long-term (20-30 min) SCS. Although high-frequency CC- and CV-SCS may be more useful for the management of somatic pain, CC-SCS may be more effective for treating complex pain systems like visceral hypersensitivity.

Delayed Autonomic Regulation during Visceral Placebo Analgesia in Patients with Irritable Bowel Syndrome

Large placebo effect is common in the treatment of irritable bowel syndrome (IBS). Autonomic dysregulation, which can be measured by heart rate variability (HRV), may play a role in the IBS pathogenesis. We aimed to compare the HRV changes during visceral placebo analgesia between healthy controls and IBS. Thirteen IBS patients and 12 sex-/age- matched controls received twice rectal balloon distension to induce visceral pain. The placebo treatment consisted of a standardized oral statement of the effectiveness of a newly-developed intravenous drug (saline actually) to relieve the visceral pain. HRV parameters, including the low frequency (LF), high frequency (HF), and ratio of LF to HF (LF/ HF), were recorded at the baseline, saline and placebo sessions. Both controls and IBS patients achieved comparable placebo effects showing similar VAS reduction after the placebo treatment. Visceral pain induced an increased LF and LF/HF (enhanced sympathetic activity and sympathovagal balance) and decreased HF (diminished vagal activity) in both groups, in which HRV changes were reversed by placebo treatment. The HRV changes upon placebo treatment were promptly observed at the first rectal balloon distension in healthy volunteers, but not until the second distension in the IBS patients. IBS patients and healthy controls can achieve comparable placebo analgesia. Both groups have similar HRV responses during visceral stimulation and placebo treatment, but with delayed HRV changes in IBS patients. Autonomic control may be impaired during visceral placebo analgesia in IBS patients.

New Therapeutic Strategy for Amino Acid Medicine: Effects of Dietary Glutamate on Gut and Brain Function

The gustatory and visceral stimulation from food regulates digestion and nutrient utilization, and free glutamate (Glu) release from food is responsible for the umami taste perception that increases food palatability. The results of recent studies reveal a variety of physiological roles for Glu. For example, luminal applications of Glu into the mouth, stomach, and intestine increase the afferent nerve activities of the glossopharyngeal nerve, the gastric branch of the vagus nerve, and the celiac branch of the vagus nerve, respectively. Additionally, luminal Glu evokes efferent nerve activation of each branch of the abdominal vagus nerve. The intragastric administration of Glu activates several brain areas (e.g., insular cortex, limbic system, and hypothalamus) and has been shown to induce flavor-preference learning in rats. Functional magnetic resonance imaging of rats has shown that the intragastric administration of Glu activates the nucleus tractus solitarius, amygdala, and lateral hypothalamus. In addition, Glu may increase flavor preference as a result of its postingestive effect. Considering these results, we propose that dietary Glu functions as a signal for the regulation of the gastrointestinal tract via the gut–brain axis and contributes to the maintenance of a healthy life.

Intrathecal Oxytocin Inhibits Visceromotor Reflex and Spinal Neuronal Responses to Noxious Distention of the Rat Urinary Bladder

Oxytocin (OXY) is a neuropeptide that has recently been recognized as an important component of descending analgesic systems. The present study sought to determine if OXY produces antinociception to noxious visceral stimulation. Urethane-anesthetized female rats had intrathecal catheters placed acutely, and the effect of intrathecal OXY on visceromotor reflexes (VMRs; abdominal muscular contractions quantified using electromyograms) to urinary bladder distension (UBD; 10-60 mm Hg, 20 seconds; transurethral intravesical catheter) was determined. The effect of OXY applied to the surface of exposed spinal cord was determined in lumbosacral dorsal horn neurons excited by UBD using extracellular recordings. Oxytocin doses of 0.15 or 1.5 μg inhibited VMRs to UBD by 37% ± 8% and 68% ± 10%, respectively. Peak inhibition occurred within 30 minutes and was sustained for at least 60 minutes. The effect of OXY was both reversed and prevented by the intrathecal administration of an OXY-receptor antagonist. Application of 0.5 mM OXY to the dorsum of the spinal cord inhibited UBD-evoked action potentials by 76% ± 12%. Consistent with the VMR studies, peak inhibition occurred within 30 minutes and was sustained for greater than 60 minutes. These results argue that intrathecal OXY produces an OXY receptor-specific antinociception to noxious UBD, with part of this effect due to inhibition of spinal dorsal horn neurons. To our knowledge, these studies provide the first evidence that intrathecal OXY may be an effective pharmacological treatment for visceral pain.

Effect of maropitant, a neurokinin 1 receptor antagonist, on anesthetic requirements during noxious visceral stimulation of the ovary in dogs

To determine the anesthetic-sparing effect of maropitant, a neurokinin 1 receptor antagonist, during noxious visceral stimulation of the ovary and ovarian ligament in dogs. Eight 1-year-old female dogs. Dogs were anesthetized with sevoflurane. Following instrumentation and stabilization, the right ovary and ovarian ligament were accessed by use of laparoscopy. The ovary was stimulated with a traction force of 6.61 N. The minimum alveolar concentration (MAC) was determined before and after 2 doses of maropitant. The sevoflurane MAC value was 2.12 ± 0.4% during stimulation without treatment (control). Administration of maropitant (1 mg/kg, IV, followed by 30 μg/kg/h, IV) decreased the sevoflurane MAC to 1.61 ± 0.4% (24% decrease). A higher maropitant dose (5 mg/kg, IV, followed by 150 μg/kg/h, IV) decreased the MAC to 1.48 ± 0.4% (30% decrease). Maropitant decreased the anesthetic requirements during visceral stimulation of the ovary and ovarian ligament in dogs. Results suggest the potential role for neurokinin 1 receptor antagonists to manage ovarian and visceral pain.

Glutamatergic activation of anterior cingulate cortex mediates the affective component of visceral pain memory in rats

Studies of both humans and animals suggest that anterior cingulate cortex (ACC) is important for processing pain perception. We identified that perigenul ACC (pACC) sensitization and enhanced visceral pain in a visceral hypersensitive rat in previous studies. Pain contains both sensory and affective dimensions. Teasing apart the mechanisms that control the neural pathways mediating pain affect and sensation in nociceptive behavioral response is a challenge. In this study, using a rodent visceral pain assay that combines the colorectal distension (CRD)-induced visceromotor response (VMR) with the conditioning place avoidance (CPA), we measured a learned behavior that directly reflects the affective component of visceral pain. When CRD was paired with a distinct environment context, the rats spent significantly less time in this compartment on the post-conditioning test days as compared with the pre-conditioning day. Effects were lasted for 14days. Bilateral pACC lesion significantly reduced CPA scores without reducing acute visceral pain behaviors (CRD-induced VMR). Bilateral administration of non-NMDA receptor antagonist CNQX or NMDA receptor antagonist AP5 into the pACC decreased the CPA scores. AP5 or CNQX at dose of 400mM produced about 70% inhibition of CRD-CPA in the day 1, 4 and 7, and completely abolished the CPA in the day 14 after conditioning. We concluded that neurons in the pACC are necessary for the “aversiveness” of visceral nociceptor stimulation. pACC activation is critical for the memory processing involved in long-term negative affective state and prediction of aversive stimuli by contextual cue.

Subcutaneous Adipose Tissue Macrophage Infiltration Is Associated With Hepatic and Visceral Fat Deposition, Hyperinsulinemia, and Stimulation of NF-κB Stress Pathway

OBJECTIVETo examine in obese young adults the influence of ethnicity and subcutaneous adipose tissue (SAT) inflammation on hepatic fat fraction (HFF), visceral adipose tissue (VAT) deposition, insulin sensitivity (SI), β-cell function, and SAT gene expression.RESEARCH DESIGN AND METHODSSAT biopsies were obtained from 36 obese young adults (20 Hispanics, 16 African Americans) to measure crown-like structures (CLS), reflecting SAT inflammation. SAT, VAT, and HFF were measured by magnetic resonance imaging, and SI and β-cell function (disposition index [DI]) were measured by intravenous glucose tolerance test. SAT gene expression was assessed using Illumina microarrays.RESULTSParticipants with CLS in SAT (n = 16) were similar to those without CLS in terms of ethnicity, sex, and total body fat. Individuals with CLS had greater VAT (3.7 ± 1.3 vs. 2.6 ± 1.6 L; P = 0.04), HFF (9.9 ± 7.3 vs. 5.8 ± 4.4%; P = 0.03), tumor necrosis factor-α (20.8 ± 4.8 vs. 16.2 ± 5.8 pg/mL; P = 0.01), fasting insulin (20.9 ± 10.6 vs. 9.7 ± 6.6 mU/mL; P < 0.001) and glucose (94.4 ± 9.3 vs. 86.8 ± 5.3 mg/dL; P = 0.005), and lower DI (1,559 ± 984 vs. 2,024 ± 829 ×10−4 min−1; P = 0.03). Individuals with CLS in SAT exhibited upregulation of matrix metalloproteinase-9 and monocyte antigen CD14 genes, as well as several other genes belonging to the nuclear factor-κB (NF-κB) stress pathway.CONCLUSIONSAdipose tissue inflammation was equally distributed between sexes and ethnicities. It was associated with partitioning of fat toward VAT and the liver and altered β-cell function, independent of total adiposity. Several genes belonging to the NF-κB stress pathway were upregulated, suggesting stimulation of proinflammatory mediators.

Integrative responses of neurons in nucleus tractus solitarius to visceral afferent stimulation and vestibular stimulation in vertical planes.

Anatomical studies have demonstrated that the vestibular nuclei project to nucleus tractus solitarius (NTS), but little is known about the effects of vestibular inputs on NTS neuronal activity. Furthermore, lesions of NTS abolish vomiting elicited by a variety of different triggering mechanisms, including vestibular stimulation, suggesting that emetic inputs may converge on the same NTS neurons. As such, an emetic stimulus that activates gastrointestinal (GI) receptors could alter the responses of NTS neurons to vestibular inputs. In the present study, we examined in decerebrate cats the responses of NTS neurons to rotations of the body in vertical planes before and after the intragastric administration of the emetic compound copper sulfate. The activity of more than one-third of NTS neurons was modulated by vertical vestibular stimulation, with most of the responsive cells having their firing rate altered by rotations in the head-up or head-down directions. These responses were aligned with head position in space, as opposed to the velocity of head movements. The activity of NTS neurons with baroreceptor, pulmonary, and GI inputs could be modulated by vertical plane rotations. However, injection of copper sulfate into the stomach did not alter the responses to vestibular stimulation of NTS neurons that received GI inputs, suggesting that the stimuli did not have additive effects. These findings show that the detection and processing of visceral inputs by NTS neurons can be altered in accordance with the direction of ongoing movements.

Pregabalin modulation of spinal and brainstem visceral nociceptive processing

Brainstem and spinal mechanisms mediating visceral nociception are investigated here using electrophysiology and immunohistochemistry techniques in a model of acute visceral pain. Colorectal distension (CRD) produced graded visceromotor responses (VMR) in normal rats, and these were facilitated by intracolonic mustard oil (MO) that generated acute visceral hyperalgesia. The neuropathic pain drug pregabalin (PGB) is thought to have state-dependent effects in attenuating neuropathic, but not acute somatic pain, likely by impairing calcium-channel trafficking. We found that systemic PGB produced antinociceptive effects on CRD-evoked VMRs in naïve rats lacking pathophysiology and in MO-pretreated rats. Systemic PGB also significantly reduced Fos labelling in lumbosacral spinal cords of rats given noxious repetitive CRD; however, PGB did not alter this measure of neural activity in the brainstem. Differential brainstem processing of noxious somatic and visceral stimuli may underlie the unique lack of state-dependent actions of PGB in this visceral pain model. Single-unit recordings in the rostral ventromedial medulla (RVM) verify that brainstem processing of somatic and visceral stimuli differs. The effects of CRD on RVM cells classed as ON, OFF, or NEUTRAL were independent of their somatic responses, with surprising changes in RVM cell activity to innocuous visceral stimulation. PGB also markedly reduced the visceral responses of RVM ON-cells to noxious CRD. These results illustrate clear differences in the central processing of visceral and somatic stimuli, yet a common role for descending modulation by brainstem activity in mediating evoked pain measures.

A dog model to study ovary, ovarian ligament and visceral pain

ObjectiveA dog model was developed to study visceral pain by stimulating the ovarian ligament. Study designProspective experimental trial. AnimalsTwelve 1-year old female hound dogs weighing 25.7 ± 3.6 kg. MethodsDogs were anesthetized with sevoflurane. The right ovary was accessed via laparoscopy. A suture was placed around the ovarian ligament and exteriorized through the abdominal wall for stimulation. The noxious stimulus consisted of pulling the ovary and ovarian ligament with a force transducer. The response to noxious stimulation was determined using the anesthetic minimum alveolar concentration requirement (MAC) for sevoflurane. The ovarian MAC was compared to the standardized somatic noxious stimulation tail clamp MAC. The results are depicted as mean ± SD and corrected to sea-level. ResultsThe stimulus–response curve during ovarian stimulation in three dogs was hyperbolic and best represented by a three-parameter logistic growth curve model. The curve plateaued at 7.12 ± 4.19 N. From the stimulus-response curve, we chose 6.61 N to test the consistency and repeatability of the model in nine dogs. The ovarian stimulation MAC for sevoflurane in these dogs was 2.16 ± 0.46%. The ovarian stimulation confidence interval and limits are comparable to the results from tail stimulation MAC. The tail stimulation MACs before and after laparoscopy surgery were not different (1.86 ± 0.28% and 1.77 ± 0.38% respectively; p > 0.05) but lower when compared to the ovarian MAC (p < 0.01). The dogs recovered from anesthesia without complications. Conclusions and clinical relevanceThe ovarian stimulation model is an adequate and repeatable means of producing visceral stimulation to determine MAC. The model may provide a humane mechanism to study the effectiveness of analgesics for acute ovarian pain.

The Intestinal Microbiota Determines Mouse Behavior and Brain BDNF Levels

Aim: Corticotropin-releasing hormone (CRH) is a major mediator of stress response in the brain-gut axis. We previously reported that peptidergic modification of CRH receptors changes visceral sensorimotor function in patients with irritable bowel syndrome (IBS). However, evidence how CRH agonist changes human brain function was lacking. We hypothesized that exogenous CRH accelerates regional brain activity during visceral stimulation in human. Methods: Sixteen healthy males aged 22.8 +/2.5 were randomly allocated into the CRH injection group and saline injection (placebo) group. A barostat bag was inserted into the colorectum and was randomly inflated with sham (0 mmHg), mild (20mmHg), or intense (40 mmHg) distention for 90s. CRH (2μg/dl) or placebo was then injected and same distention protocol was repeated. Radioactive H2[O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in regional cerebral blood flow were analyzed using statistical parametric mapping. Plasma adrenocorticotropic hormone (ACTH) and cortisol were measured at each stimulation. Results: Colorectal distention with 20 mmHg with CRH activated the right insula and parahippocampal gyrus significantly greater than that with placebo (p < 0.001). Colorectal distention with 40 mmHg with CRH activated the right dorsolateral prefrontal cortex, right orbitofrontal cortex, right insula, extended amygala, and pons significantly greater than that with placebo (p < 0.001). Twoway ANOVA of plasma ACTH showed significant CRH effect (p = 0.012), distention effect (p = 0.026) and CRH × distention interaction (p = 0.035). Post-hoc test of plasma ACTH revealed significantly higher level at 40mmHg with CRH than that with placebo (p = 0.011). Plasma cortisol showed similar pattern to plasma ACTH.Conclusion:During visceral stimulation in men, administration of CRH likely accelerates the activity of the brain regions which regulate interoception, hypothalamic regulation, stress coping, stress response, and negative emotion. These results also suggest that exogenous CRH may amplify ACTH and cortisol secretion due to colorectal distention.

Repeated and Prolonged Unperceived Visceral Stimulation is Associated With Habituation and Decrease in FMRI Signal Intensity

Repeated and Prolonged Unperceived Visceral Stimulation is Associated With Habituation and Decrease in FMRI Signal Intensity