Abnormal Neuronal Response to Rectal and Anal Stimuli in Patients Treated for Distal Rectal Cancer With High-Dose Chemoradiotherapy Followed By Watchful Waiting.

BACKGROUND: Watchful waiting in patients with rectal cancer with complete clinical response after chemoradiation therapy has gained increased popularity to avoid morbidity and mortality associated with surgery. Irradiation of the pelvis causes bowel dysfunction, but the effect on anorectal sensory function remains obscure in this patient category. OBJECTIVE: The aim of this study was to characterize the sensory pathways of the gut-brain axis in patients with rectal cancer treated solely with chemoradiation therapy (nonconventional regime/dose) compared with healthy volunteers. DESIGN: This is an explorative study. SETTINGS: Sensory evaluation by rectal distension was performed and cortical evoked potentials were recorded during rapid balloon distensions of the rectum and anal canal. Latencies and amplitudes of cortical evoked potentials were compared, and the relative amplitude of 5 spectral bands from recorded cortical evoked potentials was used as an additional proxy of neuronal processing. PATIENTS: Patients with rectal cancer solely with chemoradiation therapy (n = 13) a median of 3.2 years ago (range, 2.3-5.6 y) and healthy volunteers (n = 13) were included. MAIN OUTCOME MEASURES: Cortical evoked potentials were measured. RESULTS: Patients had 35% lower rectal capacity at a maximum tolerable volume (p = 0.007). We found no differences in rectal cortical evoked potential latencies (p = 0.09) and amplitudes (p = 0.38) between groups. However, spectral analysis of rectal cortical evoked potentials showed a decrease in θ (4-8 Hz) and an increase in ß (12-32 Hz) band activity in patients (all p < 0.001). Anal cortical potentials showed an increase in α (8-12 Hz) and ß and a decrease in γ (32-70 Hz) band activity (all p < 0.001) in patients compared with healthy volunteers. LIMITATIONS: This is an explorative study of limited size. CONCLUSIONS: Chemoradiation therapy for distal rectal cancer causes abnormal cortical processing of both anal and rectal sensory input. Such central changes may play a role in symptomatic patients, especially when refractory to local treatments. See Video Abstract at http://links.lww.com/DCR/B270. RESPUESTA NEURONAL ANORMAL A ESTÍMULOS RECTALES Y ANALES, EN PACIENTES TRATADOS POR CÁNCER RECTAL DISTAL, CON QUIMIORRADIOTERAPIA DE DOSIS ALTA, SEGUIDA DE ESPERA VIGILANTE: La espera vigilante en pacientes de cáncer rectal, con respuesta clínica completa después de la quimiorradiación, ha ganado una mayor popularidad en evitar la morbilidad y mortalidad asociadas con la cirugía. La irradiación de la pelvis causa disfunción intestinal, pero el efecto sobre la función sensorial ano-rectal sigue siendo no claro, en esta categoría de pacientes.El objetivo de este estudio, fue caracterizar las vías sensoriales del eje intestino-cerebro en pacientes con cáncer rectal, tratados únicamente con quimiorradiación (régimen / dosis no convencional), en comparación con voluntarios sanos.Es un estudio exploratorio.Se realizó una evaluación sensorial por distensión rectal y se registraron los potenciales evocados corticales, durante las distensiones rápidas con balón en recto y canal anal. Se compararon las latencias y amplitudes de los potenciales evocados corticales, y la amplitud relativa de cinco bandas espectrales registradas, de potenciales evocados corticales, se usaron como proxy adicional del procesamiento neuronal.Pacientes de cáncer rectal, únicamente con terapia de quimiorradiación (n = 13) mediana de 3.2 años (rango 2.3-5.6) y voluntarios sanos (n = 13).Potenciales evocados corticales.Pacientes tuvieron una capacidad rectal menor del 35%, al volumen máximo tolerable (p = 0.007). No encontramos diferencias en las latencias potenciales evocadas corticales rectales (p = 0.09) y amplitudes (p = 0.38) entre los grupos. Sin embargo, el análisis espectral de los potenciales evocados corticales rectales, mostró una disminución en theta (4-8 Hz) aumento en beta (12-32 Hz), y actividad en banda en pacientes (todos p <0.001). Los potenciales evocados corticales anales mostraron un aumento en alfa (8-12 Hz) y beta, disminución en gamma (32-70 Hz), y actividad en banda (todos p <0.001), en pacientes comparados a voluntarios sanos.Este es un estudio exploratorio de tamaño limitado.La quimiorradiación para el cáncer rectal distal, ocasiona procesos corticales sensoriales anormales anales y rectales. Tales cambios centrales pueden desempeñar un papel en pacientes sintomáticos, especialmente cuando son refractarios a tratamientos locales. Consulte Video Resumen en http://links.lww.com/DCR/B270.

Exaggerated potassium current reduction by oxytocin in visceral sensory neurons following chronic intermittent hypoxia.

Oxytocin (OT) from the hypothalamus is increased in several cardiorespiratory nuclei and systemically in response to a variety of stimuli and stressors, including hypoxia. Within the nucleus tractus solitarii (nTS), the first integration site for cardiorespiratory reflexes, OT enhances synaptic transmission, action potential (AP) discharge, and cardiac baroreflex gain. The hypoxic stressor obstructive sleep apnea, and its CIH animal model, elevates blood pressure and alters heart rate variability. The nTS receives sensory input from baroafferent neurons that originate in the nodose ganglia. Nodose neurons express the OT receptor (OTR) whose activation elevates intracellular calcium. However, the influence of OT on other ion channels, especially potassium channels important for neuronal activity during CIH, is less known. This study sought to determine the mechanism (s) by which OT modulates sensory afferent-nTS mediated reflexes normally and after CIH. Nodose ganglia neurons from male Sprague-Dawley rats were examined after 10d CIH (6% O2 every 3 min) or their normoxic (21% O2) control. OTR mRNA and protein were identified in Norm and CIH ganglia and was similar between groups. To examine OTR function, APs and potassium currents (IK) were recorded in dissociated neurons. Compared to Norm, after CIH OT depolarized neurons and reduced current-induced AP discharge. After CIH OT also produced a greater reduction in IK that where tetraethylammonium-sensitive. These data demonstrate after CIH OT alters ionic currents in nodose ganglia cells to likely influence cardiorespiratory reflexes and overall function.

Extensive Inhibitory Gating of Viscerosensory Signals by a Sparse Network of Somatostatin Neurons.

Integration and modulation of primary afferent sensory information begins at the first terminating sites within the CNS, where central inhibitory circuits play an integral role. Viscerosensory information is conveyed to the nucleus of the solitary tract (NTS) where it initiates neuroendocrine, behavioral, and autonomic reflex responses that ensure optimal internal organ function. This excitatory input is modulated by diverse, local inhibitory interneurons, whose functions are not clearly understood. Here we show that, in male rats, 65% of somatostatin-expressing (SST) NTS neurons also express GAD67, supporting their likely role as inhibitory interneurons. Using whole-cell recordings of NTS neurons, from horizontal brainstem slices of male and female SST-yellow fluorescent protein (YFP) and SST-channelrhodopsin 2 (ChR2)-YFP mice, we quantified the impact of SST-NTS neurons on viscerosensory processing. Light-evoked excitatory photocurrents were reliably obtained from SST-ChR2-YFP neurons (n = 16) and the stimulation-response characteristics determined. Most SST neurons (57%) received direct input from solitary tract (ST) afferents, indicating that they form part of a feedforward circuit. All recorded SST-negative NTS neurons (n = 72) received SST-ChR2 input. ChR2-evoked PSCs were largely inhibitory and, in contrast to previous reports, were mediated by both GABA and glycine. When timed to coincide, the ChR2-activated SST input suppressed ST-evoked action potentials at second-order NTS neurons, demonstrating strong modulation of primary viscerosensory input. These data indicate that the SST inhibitory network innervates broadly within the NTS, with the potential to gate viscerosensory input to powerfully alter autonomic reflex function and other behaviors.SIGNIFICANCE STATEMENT Sensory afferent input is modulated according to state. For example the baroreflex is altered during a stress response or exercise, but the basic mechanisms underpinning this sensory modulation are not fully understood in any sensory system. Here we demonstrate that the neuronal processing of viscerosensory information begins with synaptic gating at the first central synapse with second-order neurons in the NTS. These data reveal that the somatostatin subclass of inhibitory interneurons are driven by visceral sensory input to play a major role in gating viscerosensory signals, placing them within a feedforward circuit within the NTS.

Visceral-afferent signals from the cardiovascular system, but not urinary urge, affect startle eye blink.

The aim of the current study was to investigate if startle methodology is suitable to reflect urinary urgency. Eighteen healthy men were tested on two separate days, each including an ingestion of fluid until 80% of the subjective urge to micturate was reached. EMG responses to acoustic startle stimuli were assessed before and after micturition, as well as in the early and late cardiac cycle phases (230 vs. 530 ms after a cardiac R-wave). Sonographic assessment confirmed bladder-filling status. Emotional arousal, stress, urge and unpleasantness ratings, as well as mean blood pressure were higher before than after micturition. Startle eye blink responses were lower during the early than during the late cardiac cycle phase, but were not affected by bladder filling status. We conclude that startle methodology is suitable for the investigation of afferent signals from the cardiovascular system, but not to reflect urinary urgency. This result may be due to different neurophysiological mechanisms underlying afferent signals from the bladder compared to other visceral organs or interference with affective states or sympathetic activation associated with bladder filling. Notwithstanding, the present research protocol of fluid intake, sonographic assessment of the bladder, and subjective reports, can be applied to examine effects of urinary urge on physiological and psychological processes.

From psychological moments to mortality: A multidisciplinary synthesis on heart rate variability spanning the continuum of time.

Heart rate variability (HRV) indexes functioning of the vagus nerve, arguably the most important nerve in the human body. The Neurovisceral Integration Model has provided a structural framework for understanding brain-body integration, highlighting the role of the vagus in adaptation to the environment. In the present paper, we emphasise a temporal framework in which HRV may be considered a missing, structural link between psychological moments and mortality, a proposal we label as Neurovisceral Integration Across a Continuum of Time (or NIACT). This new framework places neurovisceral integration on a dimension of time, highlighting implications for lifespan development and healthy aging, and helping to bridge the gap between clearly demarcated disciplines such as psychology and epidemiology. The NIACT provides a novel framework, which conceptualizes how everyday psychological moments both affect and are affected by the vagus in ways that have long-term effects on mortality risk. We further emphasize that a longitudinal approach to understanding change in vagal function over time may yield novel scientific insights and important public health outcomes.

Spinal afferent nerve endings in visceral organs: recent advances.

Spinal afferent neurons play a major role in detection and transduction of painful stimuli from internal (visceral) organs. Recent technical advances have made it possible to visualize the endings of spinal afferent axons in visceral organs. Although it is well known that the sensory nerve cell bodies of spinal afferents reside within dorsal root ganglia (DRG), identifying their endings in internal organs has been especially challenging because of a lack of techniques to distinguish them from endings of other extrinsic and intrinsic neurons (sympathetic, parasympathetic, and enteric). We recently developed a surgical approach in live mice that allows selective labeling of spinal afferent axons and their endings, revealing a diverse array of different types of varicose and nonvaricose terminals in visceral organs, particularly the large intestine. In total, 13 different morphological types of endings were distinguished in the mouse distal large intestine, originating from lumbosacral DRG. Interestingly, the stomach, esophagus, bladder, and uterus had less diversity in their types of spinal afferent endings. Taken together, spinal afferent endings (at least in the large intestine) appear to display greater morphological diversity than vagal afferent endings that have previously been extensively studied. We discuss some of the new insights that these findings provide.

Electrophysiological characterization of human rectal afferents.

It is presumed that extrinsic afferent nerves link the rectum to the central nervous system. However, the anatomical/functional existence of such nerves has never previously been demonstrated in humans. Therefore, we aimed to identify and make electrophysiological recordings in vitro from extrinsic afferents, comparing human rectum to colon. Sections of normal rectum and colon were procured from anterior resection and right hemicolectomy specimens, respectively. Sections were pinned and extrinsic nerves dissected. Extracellular visceral afferent nerve activity was recorded. Neuronal responses to chemical [capsaicin and "inflammatory soup" (IS)] and mechanical (Von Frey probing) stimuli were recorded and quantified as peak firing rate (range) in 1-s intervals. Twenty-eight separate nerve trunks from eight rectums were studied. Of these, spontaneous multiunit afferent activity was recorded in 24 nerves. Peak firing rates increased significantly following capsaicin [median 6 (range 3-25) spikes/s vs. 2 (1-4), P < 0.001] and IS [median 5 (range 2-18) spikes/s vs. 2 (1-4), P < 0.001]. Mechanosensitive "hot spots" were identified in 16 nerves [median threshold 2.0 g (range 1.4-6.0 g)]. In eight of these, the threshold decreased after IS [1.0 g (0.4-1.4 g)]. By comparison, spontaneous activity was recorded in only 3/30 nerves studied from 10 colons, and only one hot spot (threshold 60 g) was identified. This study confirms the anatomical/functional existence of extrinsic rectal afferent nerves and characterizes their chemo- and mechanosensitivity for the first time in humans. They have different electrophysiological properties to colonic afferents and warrant further investigation in disease states.

elPBN neurons regulate rVLM activity through elPBN-rVLM projections during activation of cardiac sympathetic afferent nerves.

The external lateral parabrachial nucleus (elPBN) within the pons and rostral ventrolateral medulla (rVLM) contributes to central processing of excitatory cardiovascular reflexes during stimulation of cardiac sympathetic afferent nerves (CSAN). However, the importance of elPBN cardiovascular neurons in regulation of rVLM activity during CSAN activation remains unclear. We hypothesized that CSAN stimulation excites the elPBN cardiovascular neurons and, in turn, increases rVLM activity through elPBN-rVLM projections. Compared with controls, in rats subjected to microinjection of retrograde tracer into the rVLM, the numbers of elPBN neurons double-labeled with c-Fos (an immediate early gene) and the tracer were increased after CSAN stimulation (P < 0.05). The majority of these elPBN neurons contain vesicular glutamate transporter 3. In cats, epicardial bradykinin and electrical stimulation of CSAN increased the activity of elPBN cardiovascular neurons, which was attenuated (n = 6, P < 0.05) after blockade of glutamate receptors with iontophoresis of kynurenic acid (Kyn, 25 mM). In separate cats, microinjection of Kyn (1.25 nmol/50 nl) into the elPBN reduced rVLM activity evoked by both bradykinin and electrical stimulation (n = 5, P < 0.05). Excitation of the elPBN with microinjection of dl-homocysteic acid (2 nmol/50 nl) significantly increased basal and CSAN-evoked rVLM activity. However, the enhanced rVLM activity induced by dl-homocysteic acid injected into the elPBN was reversed following iontophoresis of Kyn into the rVLM (n = 7, P < 0.05). These data suggest that cardiac sympathetic afferent stimulation activates cardiovascular neurons in the elPBN and rVLM sequentially through a monosynaptic (glutamatergic) excitatory elPBN-rVLM pathway.

Effect of tibial nerve stimulation on bladder afferent nerve activity in a rat detrusor overactivity model.

OBJECTIVES: To study the post-stimulation effect of tibial nerve stimulation on rat bladder afferent activity, and urodynamic parameters in normal and acetic acid-induced detrusor overactivity conditions. METHODS: In urethane anesthetized male Wistar rats, the tibial nerve was stimulated for 30 min at 5 Hz, pulse width 200 µs and amplitude approximately threefold the threshold to induce a slight toe movement. The post-stimulation effect was studied by measuring afferent nerve activity of postganglionic pelvic nerve branches and various urodynamic parameters under two different conditions: (i) in physiological saline filling experiments (simulating normal bladder condition); and (ii) in acetic acid irritated bladders (simulating detrusor overactivity). RESULTS: After 30 min of tibial nerve stimulation in saline filling experiments, the bladder capacity, threshold pressure and afferent nerve activity were not significantly different from the prestimulation measurements. The instillation of 0.5% acetic acid significantly reduced the bladder capacity and increased the afferent nerve activity. Tibial nerve stimulation significantly improved the bladder capacity and suppressed the afferent nerve activity compared with prestimulation acetic acid measurements. CONCLUSIONS: Tibial nerve stimulation is able to significantly restore the bladder capacity by inhibiting afferent nerve activity in chemically irritated rat bladders. The present study provides important basic electrophysiological evidence to substantiate the clinical use of tibial nerve stimulation for treatment of symptoms related to detrusor overactivity.

Temperature differentially facilitates spontaneous but not evoked glutamate release from cranial visceral primary afferents.

Temperature is fundamentally important to all biological functions including synaptic glutamate release. Vagal afferents from the solitary tract (ST) synapse on second order neurons in the nucleus of the solitary tract, and glutamate release at this first central synapse controls autonomic reflex function. Expression of the temperature-sensitive Transient Receptor Potential Vanilloid Type 1 receptor separates ST afferents into C-fibers (TRPV1+) and A-fibers (TRPV1-). Action potential-evoked glutamate release is similar between C- and A-fiber afferents, but TRPV1 expression facilitates a second form of synaptic glutamate release in C-fibers by promoting substantially more spontaneous glutamate release. The influence of temperature on different forms of glutamate release is not well understood. Here we tested how temperature impacts the generation of evoked and spontaneous release of glutamate and its relation to TRPV1 expression. In horizontal brainstem slices of rats, activation of ST primary afferents generated synchronous evoked glutamate release (ST-eEPSCs) at constant latency whose amplitude reflects the probability of evoked glutamate release. The frequency of spontaneous EPSCs in these same neurons measured the probability of spontaneous glutamate release. We measured both forms of glutamate from each neuron during ramp changes in bath temperature of 4-5 °C. Spontaneous glutamate release from TRPV1+ closely tracked with these thermal changes indicating changes in the probability of spontaneous glutamate release. In the same neurons, temperature changed axon conduction registered as latency shifts but ST-eEPSC amplitudes were constant and independent of TRPV1 expression. These data indicate that TRPV1-operated glutamate release is independent of action potential-evoked glutamate release in the same neurons. Together, these support the hypothesis that evoked and spontaneous glutamate release originate from two pools of vesicles that are independently modulated and are distinct processes.

[The central mechanisms underlying the phenomenon of acupoint sensitization evoked by visceral nociceptive afferent].

The physiological mechanism underlying the acupoint sensitization was evaluated systemically by using the method of electric physiology at spinal cord, medulla, and thalamus levels; the dynamic change of acupoint from the relative "silence" to the relative "activation" function was explained through the study on the dynamic process of acupoint sensitization; the biological process of the therapeutic effect of acupoint stimulation was illuminated through the research of the central mechanism underlining the dose effect relationship between the sensitive acupoint and the related brain area, thus scientific evidence for the functional link between the acupoint and internal organs as well as the nature of the acupoint were provided.

Sensory nerves in lung and airways.

Sensory nerves innervating the lung and airways play an important role in regulating various cardiopulmonary functions and maintaining homeostasis under both healthy and disease conditions. Their activities conducted by both vagal and sympathetic afferents are also responsible for eliciting important defense reflexes that protect the lung and body from potential health-hazardous effects of airborne particulates and chemical irritants. This article reviews the morphology, transduction properties, reflex functions, and respiratory sensations of these receptors, focusing primarily on recent findings derived from using new technologies such as neural immunochemistry, isolated airway-nerve preparation, cultured airway neurons, patch-clamp electrophysiology, transgenic mice, and other cellular and molecular approaches. Studies of the signal transduction of mechanosensitive afferents have revealed a new concept of sensory unit and cellular mechanism of activation, and identified additional types of sensory receptors in the lung. Chemosensitive properties of these lung afferents are further characterized by the expression of specific ligand-gated ion channels on nerve terminals, ganglion origin, and responses to the action of various inflammatory cells, mediators, and cytokines during acute and chronic airway inflammation and injuries. Increasing interest and extensive investigations have been focused on uncovering the mechanisms underlying hypersensitivity of these airway afferents, and their role in the manifestation of various symptoms under pathophysiological conditions. Several important and challenging questions regarding these sensory nerves are discussed. Searching for these answers will be a critical step in developing the translational research and effective treatments of airway diseases.

Combining afferent stimulation and mirror therapy for rehabilitating motor function, motor control, ambulation, and daily functions after stroke.

BACKGROUND: Mirror therapy (MT) and mesh glove (MG) afferent stimulation may be effective in reducing motor impairment after stroke. A hybrid intervention of MT combined with MG (MT + MG) may broaden aspects of treatment benefits. OBJECTIVE: To demonstrate the comparative effects of MG + MT, MT, and a control treatment (CT) on the outcomes of motor impairments, manual dexterity, ambulation function, motor control, and daily function. METHODS: Forty-three chronic stroke patients with mild to moderate upper extremity impairment were randomly assigned to receive MT + MG, MT, or CT for 1.5 hours/day, 5 days/week for 4 weeks. Outcome measures were the Fugl-Meyer Assessment (FMA) and muscle tone measured by Myoton-3 for motor impairment and the Box and Block Test (BBT) and 10-Meter Walk Test (10 MWT) for motor function. Secondary outcomes included kinematic parameters for motor control and the Motor Activity Log and ABILHAND Questionnaire for daily function. RESULTS: FMA total scores were significantly higher and synergistic shoulder abduction during reach was less in the MT + MG and MT groups compared with the CT group. Performance on the BBT and the 10 MWT (velocity and stride length in self-paced task and velocity in as-quickly-as-possible task) were improved after MT + MG compared with MT. CONCLUSIONS: MT + MG improved manual dexterity and ambulation. MT + MG and MT reduced motor impairment and synergistic shoulder abduction more than CT. Future studies may integrate functional task practice into treatments to enhance functional outcomes in patients with various levels of motor severity. The long-term effects of MG + MT remain to be evaluated.

Effects of ghrelin on gastric distension sensitive neurons and gastric motility in the lateral septum and arcuate nucleus regulation.

BACKGROUND: Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) and a peptide hormone that promotes food intake and gastric motility. Our aims are to explore the effects of ghrelin on gastric distension (GD) sensitive neurons in the lateral septum, and the possible regulation of gastric motility by ghrelin through the hypothalamic arcuate nucleus (ARC). METHODS: Single-unit discharges were recorded, extracellularly, and the gastric motility was monitored by the administration of ghrelin in the lateral septum. The projection of nerve fiber and expression of ghrelin were observed by retrograde tracer and fluo-immunohistochemistry staining. The expression of GHS-R and ghrelin was determined by real-time polymerase chain reaction and western blotting analysis. RESULTS: There were GD neurons in the lateral septum. The administration of ghrelin could excite both GD-excitatory (GD-E) and GD-inhibitory (GD-I) neurons in the lateral septum. Gastric motility was significantly enhanced by the administration of ghrelin in the lateral septum in a dose-dependent manner. Pretreatment with [D-Lys-3]-GHRP-6, however, could completely abolish the ghrelin-induced effects. Electrical stimulation of the ARC could significantly excite the response of GD neurons to ghrelin, increase ghrelin protein expression in the lateral septum and promote gastric motility. Nevertheless, these effects could be mitigated by pretreatment of [D-Lys-3]-GHRP-6. Electrical lesion of the lateral septum resulted in decreased gastric motility. The GHS-R and Ghrelin/FG-double labeled neurons were observed in the lateral septum and ARC, respectively. CONCLUSIONS: It is suggested that the lateral septum may receive afferent information from the gastrointestinal tract and promote gastric motility. Ghrelin plays an important role in promoting gastric motility in the lateral septum. The ARC may be involved in the regulation of the lateral septum's influence on gastric motility.

Shugan-decoction relieves visceral hyperalgesia and reduces TRPV1 and SP colon expression.

AIM: To evaluate the therapeutic effect of Shugan-decoction (SGD) on visceral hyperalgesia and colon gene expressions using a rat model. METHODS: Ninety-six adult male Wistar rats were randomized into six equal groups for assessment of SGD effects on psychological stress-induced changes using the classic water avoidance stress (WAS) test. Untreated model rats were exposed to chronic (1 h/d for 10 d consecutive) WAS conditions; experimental treatment model rats were administered with intragastric SGD at 1 h before WAS on consecutive days 4-10 (low-dose: 0.1 g/mL; mid-dose: 0.2 g/mL; high-dose: 0.4 g/mL); control treatment model rats were similarly administered with the irritable bowel syndrome drug, dicetel (0.0042 g/mL); untreated normal control rats received no drug and were not subjected to the WAS test. At the end of the 10-d WAS testing period, a semi-quantitative measurement of visceral sensitivity was made by assessing the abdominal withdrawal reflex (AWR) to colorectal balloon-induced distension (at 5 mmHg increments) to determine the pain pressure threshold (PPT, evidenced by pain behavior). Subsequently, the animals were sacrificed and colonic tissues collected for assessment of changes in expressions of proteins related to visceral hypersensitivity (transient receptor potential vanilloid 1, TRPV1) and sustained visceral hyperalgesia (substance P, SP) by immunohistochemistry and real-time polymerase chain reaction. Inter-group differences were assessed by paired t test or repeated measures analysis of variance. RESULTS: The WAS test successfully induced visceral hypersensitivity, as evidenced by a significantly reduced AWR pressure in the untreated model group as compared to the untreated normal control group (190.4 ± 3.48 mmHg vs 224.0 ± 4.99 mmHg, P < 0.001). SGD treatments at mid-dose and high-dose and the dicetel treatment significantly increased the WAS-reduced PPT (212.5 ± 2.54, 216.5 ± 3.50 and 217.7 ± 2.83 mmHg respectively, all P < 0.001); however, the low-dose SGD treatment produced no significant effect on the WAS-reduced PPT (198.3 ± 1.78 mmHg, P > 0.05). These trends corresponded to the differential expressions observed for both TRPV1 protein (mid-dose: 1.64 ± 0.08 and high-dose: 1.69 ± 0.12 vs untreated model: 3.65 ± 0.32, P < 0.001) and mRNA (0.44 ± 0.16 and 0.15 ± 0.03 vs 1.39 ± 0.15, P < 0.001) and SP protein (0.99 ± 0.20 and 1.03 ± 0.23 vs 2.03 ± 0.12, P < 0.01) and mRNA (1.64 ± 0.19 and 1.32 ± 0.14 vs 2.60 ± 0.33, P < 0.05). These differential expressions of TRPV1 and SP related to mid- and high-dose SGD treatments were statistically similar to the changes induced by dicetel treatment. No signs of overt damage to the rat system were observed for any of the SGD dosages. CONCLUSION: Shugan-decoction can reduce chronic stress-induced visceral hypersensitivity in rats, and the regulatory mechanism may involve mediating the expressions of TRPV1 and SP in colon tissues.

Increase in neuroexcitability of unmyelinated C-type vagal ganglion neurons during initial postnatal development of visceral afferent reflex functions.

BACKGROUND: Baroreflex gain increase up closely to adult level during initial postnatal weeks, and any interruption within this period will increase the risk of cardiovascular problems in later of life span. We hypothesize that this short period after birth might be critical for postnatal development of vagal ganglion neurons (VGNs). METHODS: To evaluate neuroexcitability evidenced by discharge profiles and coordinate changes, ion currents were collected from identified A- and C-type VGNs at different developmental stages using whole-cell patch clamping. RESULTS: C-type VGNs underwent significant age-dependent transition from single action potential (AP) to repetitive discharge. The coordinate changes between TTX-S and TTX-R Na(+) currents were also confirmed and well simulated by computer modeling. Although 4-AP or iberiotoxin age dependently increased firing frequency, AP duration was prolonged in an opposite fashion, which paralleled well with postnatal changes in 4-AP- and iberiotoxin-sensitive K(+) current activity, whereas less developmental changes were verified in A-types. CONCLUSION: These data demonstrate for the first time that the neuroexcitability of C-type VGNs increases significantly compared with A-types within initial postnatal weeks evidenced by AP discharge profiles and coordinate ion channel changes, which explain, at least in part, that initial postnatal weeks may be crucial for ontogenesis in visceral afferent reflex function.

Anandamide, cannabinoid type 1 receptor, and NMDA receptor activation mediate non-Hebbian presynaptically expressed long-term depression at the first central synapse for visceral afferent fibers.

Presynaptic long-term depression (LTD) of synapse efficacy generally requires coordinated activity between presynaptic and postsynaptic neurons and a retrograde signal synthesized by the postsynaptic cell in an activity-dependent manner. In this study, we examined LTD in the rat nucleus tractus solitarii (NTS), a brainstem nucleus that relays homeostatic information from the internal body to the brain. We found that coactivation of N-methyl-D-aspartate receptors (NMDARs) and type 1 cannabinoid receptors (CB1Rs) induces LTD at the first central excitatory synapse between visceral fibers and NTS neurons. This LTD is presynaptically expressed. However, neither postsynaptic activation of NMDARs nor postsynaptic calcium influx are required for its induction. Direct activation of NMDARs triggers cannabinoid-dependent LTD. In addition, LTD is unaffected by blocking 2-arachidonyl-glycerol synthesis, but its induction threshold is lowered by preventing fatty acid degradation. Altogether, our data suggest that LTD in NTS neurons may be entirely expressed at the presynaptic level by local anandamide synthesis.

[The visceral theory of sleep].

The review focuses on the studies which were undertaken in order to check our visceral hypothesis of sleep. The review presents also independent studies, results of which are in good agreement with this hypothesis. The visceral hypothesis proposes that during sleep central nervous system including all cortical areas switches from the processing of the exteroceptive information (visual, somatosensory and so on) to the processing of the interoceptive information coming from all visceral systems of an organism. This change of the cortical afferentation during sleep proposes simultaneous change of the directions of the efferent cortical information flows. In wakefulness these flows were directed towards the structures involved in organization of behavior. During sleep they will be redirected towards the structures undertaking visceral regulation. Analysis of the visceral hypothesis of sleep shows that many disorders connected with sleep-wake cycle can be explained by asynchronous switches of the cortical afferent and efferent information flows.

Extrinsic primary afferent signalling in the gut.

Visceral sensory neurons activate reflex pathways that control gut function and also give rise to important sensations, such as fullness, bloating, nausea, discomfort, urgency and pain. Sensory neurons are organised into three distinct anatomical pathways to the central nervous system (vagal, thoracolumbar and lumbosacral). Although remarkable progress has been made in characterizing the roles of many ion channels, receptors and second messengers in visceral sensory neurons, the basic aim of understanding how many classes there are, and how they differ, has proven difficult to achieve. We suggest that just five structurally distinct types of sensory endings are present in the gut wall that account for essentially all of the primary afferent neurons in the three pathways. Each of these five major structural types of endings seems to show distinctive combinations of physiological responses. These types are: 'intraganglionic laminar' endings in myenteric ganglia; 'mucosal' endings located in the subepithelial layer; 'muscular-mucosal' afferents, with mechanosensitive endings close to the muscularis mucosae; 'intramuscular' endings, with endings within the smooth muscle layers; and 'vascular' afferents, with sensitive endings primarily on blood vessels. 'Silent' afferents might be a subset of inexcitable 'vascular' afferents, which can be switched on by inflammatory mediators. Extrinsic sensory neurons comprise an attractive focus for targeted therapeutic intervention in a range of gastrointestinal disorders.

Monoaminergic modulation of spinal viscero-sympathetic function in the neonatal mouse thoracic spinal cord.

Descending serotonergic, noradrenergic, and dopaminergic systems project diffusely to sensory, motor and autonomic spinal cord regions. Using neonatal mice, this study examined monoaminergic modulation of visceral sensory input and sympathetic preganglionic output. Whole-cell recordings from sympathetic preganglionic neurons (SPNs) in spinal cord slice demonstrated that serotonin, noradrenaline, and dopamine modulated SPN excitability. Serotonin depolarized all, while noradrenaline and dopamine depolarized most SPNs. Serotonin and noradrenaline also increased SPN current-evoked firing frequency, while both increases and decreases were seen with dopamine. In an in vitro thoracolumbar spinal cord/sympathetic chain preparation, stimulation of splanchnic nerve visceral afferents evoked reflexes and subthreshold population synaptic potentials in thoracic ventral roots that were dose-dependently depressed by the monoamines. Visceral afferent stimulation also evoked bicuculline-sensitive dorsal root potentials thought to reflect presynaptic inhibition via primary afferent depolarization. These dorsal root potentials were likewise dose-dependently depressed by the monoamines. Concomitant monoaminergic depression of population afferent synaptic transmission recorded as dorsal horn field potentials was also seen. Collectively, serotonin, norepinephrine and dopamine were shown to exert broad and comparable modulatory regulation of viscero-sympathetic function. The general facilitation of SPN efferent excitability with simultaneous depression of visceral afferent-evoked motor output suggests that descending monoaminergic systems reconfigure spinal cord autonomic function away from visceral sensory influence. Coincident monoaminergic reductions in dorsal horn responses support a multifaceted modulatory shift in the encoding of spinal visceral afferent activity. Similar monoamine-induced changes have been observed for somatic sensorimotor function, suggesting an integrative modulatory response on spinal autonomic and somatic function.