Central neural mechanisms mediating human visceral hypersensitivity

Although visceral hypersensitivity is thought to be important in generating symptoms in functional gastrointestinal disorders, the neural mechanisms involved are poorly understood. We recently showed that central sensitization (hyperexcitability of spinal cord sensory neurones) may play an important role. In this study, we demonstrate that after a 30-min infusion of 0.15 M HCl acid into the healthy human distal esophagus, we see a reduction in the pain threshold to electrical stimulation of the non-acid-exposed proximal esophagus (9.6 ± 2.4 mA) and a concurrent reduction in the latency of the N1 and P2 components of the esophageal evoked potentials (EEP) from this region (10.4 ± 2.3 and 15.8 ± 5.3 ms, respectively). This reduced EEP latency indicates a central increase in afferent pathway velocity and therefore suggests that hyperexcitability within the central visceral pain pathway contributes to the hypersensitivity within the proximal, non-acid-exposed esophagus (secondary hyperalgesia/allodynia). These findings provide the first electrophysiological evidence that central sensitization contributes to human visceral hypersensitivity.

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Predisposition of Neonatal Maternal Separation to Visceral Hypersensitivity via Downregulation of Small-Conductance Calcium-Activated Potassium Channel Subtype 2 (SK2) in Mice

Neural Plasticity ◽

10.1155/2020/8876230 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Ke Wu ◽

Jing-hua Gao ◽

Rong Hua ◽

Xiao-han Peng ◽

Hui Wang ◽

...

Keyword(s):

Potassium Channel ◽

Pain Threshold ◽

Maternal Separation ◽

Visceral Pain ◽

Neuronal Firing ◽

Visceral Hypersensitivity ◽

Anxiety And Depression ◽

Firing Rates ◽

Calcium Activated Potassium Channel ◽

Small Conductance

Background. Visceral hypersensitivity is a common occurrence of gastrointestinal diseases such as irritable bowel syndrome (IBS), wherein early-life stress (ELS) may have a high predisposition to the development of visceral hypersensitivity in adulthood, with the specific underlying mechanism still elusive. Herein, we assessed the potential effect of small-conductance calcium-activated potassium channel subtype 2 (SK2) in the spinal dorsal horn (DH) on the pathogenesis of visceral hypersensitivity induced by maternal separation (MS) in mice. Methods. Neonatal mice were subjected to the MS paradigm, an established ELS model. In adulthood, the visceral pain threshold and the abdominal withdrawal reflex (AWR) were measured with an inflatable balloon. The elevated plus maze, open field test, sucrose preference test, and forced swim test were employed to evaluate the anxiety- and depression-like behaviors. The expression levels of SK2 in the spinal DH were determined by immunofluorescence and western blotting. The mRNA of SK2 and membrane palmitoylated protein 2 (MPP2) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Electrophysiology was applied to evaluate the neuronal firing rates and SK2 channel-mediated afterhyperpolarization current (IAHP). The interaction between MPP2 and SK2 was validated by coimmunoprecipitation. Results. In contrast to the naïve mice, ethological findings in MS mice revealed lowered visceral pain threshold, more evident anxiety- and depression-like behaviors, and downregulated expression of membrane SK2 protein and MPP2 protein. Moreover, electrophysiological results indicated increased neuronal firing rates and decreased IAHP in the spinal DH neurons. Nonetheless, intrathecal injection of the SK2 channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) in MS mice could reverse the electrophysiological alterations and elevate the visceral pain threshold. In the naïve mice, administration of the SK2 channel blocker apamin abated IAHP and elevated spontaneous neuronal firing rates in the spinal DH neurons, reducing the visceral pain threshold. Finally, disruption of the MPP2 expression by small interfering RNA (siRNA) could amplify visceral hypersensitivity in naïve mice. Conclusions. ELS-induced visceral pain and visceral hypersensitivity are associated with the underfunction of SK2 channels in the spinal DH.

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Imipramine decreases oesophageal pain perception in human male volunteers

Gut ◽

10.1136/gut.42.6.807 ◽

1998 ◽

Vol 42 (6) ◽

pp. 807-813 ◽

Cited By ~ 85

Author(s):

P L Peghini ◽

P O Katz ◽

D O Castell

Keyword(s):

Analgesic Effect ◽

Pain Threshold ◽

Pain Perception ◽

Visceral Pain ◽

Functional Gastrointestinal Disorders ◽

Normal Male ◽

Visceral Hyperalgesia ◽

Double Blind ◽

Pain Thresholds ◽

Male Volunteers

Background—Visceral hyperalgesia is a hallmark of functional gastrointestinal disorders. Antidepressants improve symptoms in these patients, although their mode of action is unclear. Antidepressant, anticholinergic, and analgesic mechanisms have been proposed.Aims—To investigate whether imipramine, which has a visceral analgesic effect, increases pain thresholds to experimental visceral pain.Methods—Visceral perception for first sensation and pain was measured with intraoesophageal balloon distension in 15 male volunteers. The effect of imipramine was studied in a double blind, placebo controlled, crossover study. Imipramine was given in ascending doses for 12 days (25 mg days 1–3, 50 mg days 4–6, 75 mg days 7–12), with oesophageal perception studied on day 13.Results—Inflation volumes and intraballoon pressures at first sensation were not different between placebo and imipramine. Balloon inflation volume at pain threshold was higher on imipramine (p=0.015). Median intraballoon pressures were not different at pain threshold for placebo and imipramine. Oesophageal wall compliance was not affected by imipramine.Conclusion—Increased pain thresholds on imipramine in this group of normal male volunteers in the absence of changes in oesophageal tone imply the presence of a visceral analgesic effect.

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Pain Evoked by Electrical Stimulation of the Prepyloric Region of the Stomach: Cutaneous Sensibility Changes in the Referred Pain Area

Pain Research and Management ◽

10.1155/1999/516320 ◽

1999 ◽

Vol 4 (3) ◽

pp. 131-137 ◽

Cited By ~ 10

Author(s):

Asbjørn M Drewes ◽

Henrik B Krarup ◽

Jesper B Hansen ◽

Ulrik Tage-Jensen ◽

Lars Arendt-Nielsen

Keyword(s):

Electrical Stimulation ◽

Pain Threshold ◽

Visceral Pain ◽

Control Area ◽

Referred Pain ◽

Detection Thresholds ◽

Patient Groups ◽

Pain Detection ◽

Pain Area ◽

Stimulation Of

OBJECTIVE:To investigate the pain threshold and the referred pain areas to electrical stimulation of the prepyloric region of the stomach, and the cutaneous sensibility in the referred pain areas.DESIGN:Eight healthy males volunteered for the study. To identify the area of referred pain, all subjects participated in a study using the same model four months previously. During gastroscopy, repeated electrical burst stimuli were delivered in four adjacent prepyloric sites of the stomach, and the pain detection thresholds (PDTs) together with the area of pain referral were determined. Before, during and after continuous electrical painful stimuli delivered in the prepyloric region, the cutaneous sensitivities in the referred pain area and a control area on the chest were characterized using electrical, heat, touch and pinprick stimuli.RESULTS:The PDTs in the four prepyloric areas were not different and the location of the referred pain was reproducible. During the nociceptive visceral stimuli, hyperalgesia to heat stimulation was detected in the referred pain area compared with the control area, but the thresholds for electrical, touch and pinprick stimulations did not change.CONCLUSIONS:The reproducible pain thresholds in adjacent prepyloric sites make future analysis in patient groups possible because the precise site of stimulation can vary without changing the sensibility. The modality-specific somatosensory changes in the referred pain areas further indicate that visceral pain can cause differentiated sensory changes. Modality-specific sensibility changes are also seen in referred areas to muscle pain. Thus, the model may increase the information on viscerocutaneous convergence phenomena in humans.

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Neural mechanisms of hepatic blood flow response to noxious mechanical stimulation of skin in anesthetized rats

Neuroscience Research ◽

10.1016/s0168-0102(00)81890-8 ◽

2000 ◽

Vol 38 ◽

pp. S174

Author(s):

K Enomoto

Keyword(s):

Blood Flow ◽

Hepatic Blood Flow ◽

Mechanical Stimulation ◽

Neural Mechanisms ◽

Blood Flow Response ◽

Flow Response ◽

Anesthetized Rats ◽

Noxious Mechanical Stimulation ◽

Stimulation Of

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A38 TRPV1 VISCERAL AFFERENTS CONTROL CENTRAL SENSITIZATION IN IBD

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwab002.036 ◽

2021 ◽

Vol 4 (Supplement_1) ◽

pp. 278-279

Author(s):

M Defaye ◽

N Abdullah ◽

M Iftinca ◽

C Altier

Keyword(s):

Chronic Pain ◽

Central Sensitization ◽

Microglial Activation ◽

Visceral Pain ◽

Purinergic Signaling ◽

Designer Drugs ◽

Visceral Afferents ◽

Peripheral Sensitization ◽

Specific Expression

Abstract Background Long-lasting changes in neural pain circuits precipitate the transition from acute to chronic pain in patients living with inflammatory bowel diseases (IBDs). While significant improvement in IBD therapy has been made to reduce inflammation, a large subset of patients continues to suffer throughout quiescent phases of the disease, suggesting a high level of plasticity in nociceptive circuits during acute phases. The establishment of chronic visceral pain results from neuroplasticity in nociceptors first, then along the entire neural axis, wherein microglia, the resident immune cells of the central nervous system, are critically involved. Our lab has shown that spinal microglia were key in controlling chronic pain state in IBD. Using the Dextran Sodium Sulfate (DSS) model of colitis, we found that microglial G-CSF was able to sensitize colonic nociceptors that express the pain receptor TRPV1. While TRPV1+ nociceptors have been implicated in peripheral sensitization, their contribution to central sensitization via microglia remains unknown. Aims To investigate the role of TRPV1+ visceral afferents in microglial activation and chronic visceral pain. Methods We generated DREADD (Designer Receptors Exclusively Activated by Designer Drugs) mice in which TRPV1 sensory neurons can be inhibited (TRPV1-hM4Di) or activated (TRPV1-hM3Dq) in a time and tissue specific manner using the inert ligand Clozapine-N-Oxide (CNO). To test the inhibition of TRPV1 neurons in DSS-induced colitis, TRPV1-hM4Di mice were treated with DSS 2.5% or water for 7 days and received vehicle or CNO i.p. injection twice daily. To activate TRPV1 visceral afferents, TRPV1-hM3Dq mice received vehicle or CNO daily for 7 days, by oral gavage. After 7 days of treatment, visceral pain was evaluated by colorectal distension and spinal cords tissues were harvested to measure microglial activation. Results Our data validated the nociceptor specific expression and function of the DREADD in TRPV1-Cre mice. Inhibition of TRPV1 visceral afferents in DSS TRPV1-hM4Di mice was able to prevent the colitis-induced microglial activation and thus reduce visceral hypersensitivity. In contrast, activation of TRPV1 visceral afferents in TRPV1-hM3Dq mice was sufficient to drive microglial activation in the absence of colitis. Analysis of the proalgesic mediators derived from activated TRPV1-hM3Dq neurons identified ATP as a key factor of microglial activation. Conclusions Overall, these data provide novel insights into the mechanistic understanding of the gut/brain axis in chronic visceral pain and suggest a role of purinergic signaling that could be harnessed for testing effective therapeutic approaches to relieve pain in IBD patients. Funding Agencies CCCACHRI (Alberta Children’s Hospital Research Institute) and CSM (Cumming School of Medicine) postdoctoral fellowship

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Tetrodotoxin: A New Strategy to Treat Visceral Pain?

Toxins ◽

10.3390/toxins13070496 ◽

2021 ◽

Vol 13 (7) ◽

pp. 496

Author(s):

Ana Campos-Ríos ◽

Lola Rueda-Ruzafa ◽

Salvador Herrera-Pérez ◽

Paula Rivas-Ramírez ◽

José Antonio Lamas

Keyword(s):

Action Potentials ◽

Channel Blocker ◽

Visceral Pain ◽

Visceral Hypersensitivity ◽

Afferent Neurons ◽

Sodium Channel Blocker ◽

Voltage Gated Sodium Channels ◽

New Strategy ◽

Specific Receptors

Visceral pain is one of the most common symptoms associated with functional gastrointestinal (GI) disorders. Although the origin of these symptoms has not been clearly defined, the implication of both the central and peripheral nervous systems in visceral hypersensitivity is well established. The role of several pathways in visceral nociception has been explored, as well as the influence of specific receptors on afferent neurons, such as voltage-gated sodium channels (VGSCs). VGSCs initiate action potentials and dysfunction of these channels has recently been associated with painful GI conditions. Current treatments for visceral pain generally involve opioid based drugs, ≠≠which are associated with important side-effects and a loss of effectiveness or tolerance. Hence, efforts have been intensified to find new, more effective and longer-lasting therapies. The implication of VGSCs in visceral hypersensitivity has drawn attention to tetrodotoxin (TTX), a relatively selective sodium channel blocker, as a possible and promising molecule to treat visceral pain and related diseases. As such, here we will review the latest information regarding this toxin that is relevant to the treatment of visceral pain and the possible advantages that it may offer relative to other treatments, alone or in combination.

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Functional disruption of cortical cingulate activity attenuates visceral hypersensitivity and anxiety induced by acute experimental colitis

Scientific Reports ◽

10.1038/s41598-021-81256-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lukas Brenner ◽

Leah Zerlin ◽

Linette Liqi Tan

Keyword(s):

Visceral Pain ◽

Experimental Colitis ◽

Visceral Hypersensitivity ◽

Cortical Activation ◽

Anterior Cingulate ◽

Pathological Feature ◽

Activation Patterns ◽

Bowel Disorders ◽

Noxious Mechanical Stimulation ◽

Underlying Mechanisms

AbstractVisceral pain is a highly complex experience and is the most common pathological feature in patients suffering from inflammatory gastrointestinal disorders. Whilst it is increasingly recognized that aberrant neural processing within the gut-brain axis plays a key role in development of neurological symptoms, the underlying mechanisms remain largely unknown. Here, we investigated the cortical activation patterns and effects of non-invasive chemogenetic suppression of cortical activity on visceral hypersensitivity and anxiety-related phenotypes in a well-characterized mouse model of acute colitis induced by dextran sulfate sodium (DSS). We found that within the widespread cortical network, the mid-cingulate cortex (MCC) was consistently highly activated in response to innocuous and noxious mechanical stimulation of the colon. Furthermore, during acute experimental colitis, impairing the activity of the MCC successfully alleviated visceral hypersensitivity, anxiety-like behaviors and visceromotor responses to colorectal distensions (CRDs) via downregulating the excitability of the posterior insula (PI), somatosensory and the rostral anterior cingulate cortices (rACC), but not the prefrontal or anterior insula cortices. These results provide a mechanistic insight into the central cortical circuits underlying painful visceral manifestations and implicate MCC plasticity as a putative target in cingulate-mediated therapies for bowel disorders.

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Acupuncture Affects Regional Blood Flow in Various Organs

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nem051 ◽

2008 ◽

Vol 5 (2) ◽

pp. 145-151 ◽

Cited By ~ 53

Author(s):

Sae Uchida ◽

Harumi Hotta

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

The Body ◽

Neural Mechanisms ◽

Uterine Blood Flow ◽

Afferent Pathway ◽

Antidromic Activation ◽

Efferent Nerve ◽

Afferent Nerves ◽

Cortical Cerebral Blood Flow

In this review, our recent studies using anesthetized animals concerning the neural mechanisms of vasodilative effect of acupuncture-like stimulation in various organs are briefly summarized. Responses of cortical cerebral blood flow and uterine blood flow are characterized as non-segmental and segmental reflexes. Among acupuncture-like stimuli delivered to five different segmental areas of the body; afferent inputs to the brain stem (face) and to the spinal cord at the cervical (forepaw), thoracic (chest or abdomen), lumbar (hindpaw) and sacral (perineum) levels, cortical cerebral blood flow was increased by stimuli to face, forepaw and hindpaw. The afferent pathway of the responses is composed of somatic groups III and IV afferent nerves and whose efferent nerve pathway includes intrinsic cholinergic vasodilators originating in the basal forebrain. Uterine blood flow was increased by cutaneous stimulation of the hindpaw and perineal area, with perineal predominance. The afferent pathway of the response is composed of somatic group II, III and IV afferent nerves and the efferent nerve pathway includes the pelvic parasympathetic cholinergic vasodilator nerves. Furthermore, we briefly summarize vasodilative regulation of skeletal muscle blood flow via a calcitonin gene-related peptide (CGRP) induced by antidromic activation of group IV somatic afferent nerves. These findings in healthy but anesthetized animals may be applicable to understanding the neural mechanisms improving blood flow in various organs following clinical acupuncture.

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Evidence for diminished visceral pain with aging: studies using graded intraesophageal balloon distension

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1997.272.1.g1 ◽

1997 ◽

Vol 272 (1) ◽

pp. G1-G3 ◽

Cited By ~ 10

Author(s):

H. Lasch ◽

D. O. Castell ◽

J. A. Castell

Keyword(s):

Pain Threshold ◽

Visceral Pain ◽

Threshold Value ◽

The Elderly ◽

Mean Value ◽

Elderly Subjects ◽

Pain Thresholds ◽

Age Related ◽

Balloon Distension ◽

Intraesophageal Balloon Distension

Graded intraesophageal balloon distension (IEBD) has been utilized in the past to evaluate esophageal pain thresholds. With use of a technique that we have found to provide reproducible results for pain thresholds, two groups of normal individuals without esophageal symptoms or diabetes were studied. Group 1 included 10 "young" (age < 65 yr) individuals (mean age 27 yr, range 18-57 yr). Group 2 included 17 individuals age 65 yr or greater (mean age 72.5 yr, range 65-87 yr). Catheters with latex balloons (Wilson-Cook) were used in all 27 subjects with the balloon located 10 cm above the lower esophageal sphincter. Sequential inflations of 2-ml increments were performed until a total volume of 2 ml above the point of pain or to a maximum of 30 ml was reached. A series of two sequential inflations were performed on each subject on the day of the testing, and the mean value was taken to indicate pain threshold volumes for all 27 subjects. In the group of elderly volunteers, 5 subjects felt no pain even at the maximum inflatable volume of the balloon (30 ml) and were assigned a maximum threshold value of 30 ml. Mean pain threshold volumes for the young subjects was 17 +/- 0.8 ml of air (+/- SE) and for the elderly subjects was 27 +/- 1.4 ml (P < 0.01 and 95% confidence interval = 7.1-13.3). Our conclusion is that IEBD results in the esophagus indicate an age-related decrease in human visceral pain threshold.

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