Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments.

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.

The Gut Microbiota and Chronic Pain.

PURPOSE OF REVIEW: To examine the effects and interactions between gut microbia and chronic pain. RECENT FINDINGS: The gut microbiome has been an area of interest in both the scientific and general audience due to a growing body of evidence suggesting its influence in a variety of health and disease states. Communication between the central nervous system (CNS) and gut microbiome is said to be bidirectional, in what is referred to as the gut-brain axis. Chronic pain is a prevalent costly personal and public health burden and so, there is a vested interest in devising safe and efficacious treatments. Numerous studies, many of which are animal studies, have been conducted to examine the gut microbiome's role in the pathophysiology of chronic pain states, such as neuropathy, inflammation, visceral pain, etc. As the understanding of this relationship grows, so does the potential for therapeutic targeting of the gut microbiome in chronic pain.

Interventional Treatment Modalities for Chronic Abdominal and Pelvic Visceral Pain.

PURPOSE OF REVIEW: Chronic abdominal and pelvic visceral pain is an oftentimes difficult to treat pain condition that requires a multidisciplinary approach. This article specifically reviews the interventional treatment options for pain resulting from visceral abdominal and pelvic pain. RECENT FINDINGS: Sympathetic nerve blocks are the main interventional option for the treatment of chronic abdominal and pelvic visceral pain. Initially, nerve blocks are performed, and subsequently, neurolytic injections (alcohol or phenol) are longer term options. This review describes different techniques for sympathetic blockade. Neuromodulation is a potential option via dorsal column stimulation or dorsal root ganglion stimulation. Finally, intrathecal drug delivery is sometimes appropriate for refractory cases. This paper will review interventional options for the treatment of chronic abdominal and pelvic visceral pain.

[From gut feeling to visceral pain : Effects of negative expectations in the context of the gut-brain axis]. / Vom Bauchgefühl zum viszeralen Schmerz : Effekte negativer Erwartungen im Kontext der Darm-Gehirn-Achse.

Disturbances of the gut-brain axis are characterized by complex dysfunctions on peripheral and central nervous system levels, which can contribute to visceral hypervigilance and hyperalgesia and imprint visceral pain. Numerous cognitive, emotional and psychoneurobiological factors are involved in visceral pain modulation, which in the psychosocial treatment concept can have a positive as well as a negative impact on the experience of visceral pain. Nocebo effects induced by negative expectations are of high clinical relevance in acute and especially in chronic visceral pain but the underlying mechanisms remain insufficiently understood. Verbal instructions, previous experiences and learning processes as well as emotional factors, such as fear and stress contribute to the development and maintenance of negative expectation effects. Targeted communication strategies, a sensitive use of information in the clarification and positive environmental context conditions can contribute to establishing an adequate expectation management and minimize negative expectation effects in the clinical practice. At the same time, translational research approaches are required to gain further insights into the mediators and moderators of negative expectation effects and to transfer these into clinical practice. In this way the treatment of patients with disorders of the gut-brain communication can be improved.

Transcranial direct current stimulation relieves visceral hypersensitivity via normalizing GluN2B expression and neural activity in anterior cingulate cortex.

Irritable bowel syndrome (IBS) is one of the most common challenging diseases for clinical treatment. The aim of this study is to investigate whether transcranial direct current stimulation (tDCS) has analgesic effect on visceral hypersensitivity (VH) in an animal model of IBS as well as the underlying mechanism. As the activation of GluN2B in anterior cingulate cortex (ACC) takes part in VH, we examined whether and how GluN2B in ACC takes part in the effect of tDCS. Neonatal maternal deprivation (NMD), a valuable experimental model to study the IBS pathophysiology, was used to induce visceral hypersensitivity of rats. We quantified VH as colorectal distention threshold and performed patch-clamp recordings of ACC neurons. The expression of GluN2B were determined by RT-qPCR and Western blotting. The GluN2B antagonist Ro 25-6981 was microinjected into the rostral and caudal ACC. tDCS was performed for 7 consecutive days. It was found that NMD decreased expression of GluN2B, which could be obviously reversed by tDCS. Injection of Ro 25-6981 into rostral and caudal ACC of normal rats induced VH and also reversed the analgesic effect of tDCS. Our data sheds light on the nonpharmacological therapy for chronic VH in pathological states such as IBS.NEW & NOTEWORTHY Irritable bowel syndrome (IBS) is a gastrointestinal disease characterized by visceral hypersensitivity. This study showed a decrease of GluN2B expression and neural activity in ACC of IBS-model rats, which could be obviously reversed by tDCS. In addition, blockade of GluN2B in rostral and caudal ACC induced VH of normal rats. Furthermore, analgesic effect of tDCS on NMD rats was reversed by GluN2B antagonist.

Spinal Cord Stimulation for Visceral Pain: Present Approaches and Future Strategies.

INTRODUCTION: The introduction of successful neuromodulation strategies for managing chronic visceral pain lag behind what is now treatment of choice in refractory chronic back and extremity pain for many providers in the United States and Europe. Changes in public policy and monetary support to identify nonopioid treatments for chronic pain have sparked interest in alternative options. In this review, we discuss the scope of spinal cord stimulation (SCS) for visceral pain, its limitations, and the potential role for new intradural devices of the type that we are developing in our laboratories, which may be able to overcome existing challenges. METHODS: A review of the available literature relevant to this topic was performed, with particular focus on the pertinent neuroanatomy and uses of spinal cord stimulation systems in the treatment of malignant and nonmalignant gastrointestinal, genitourinary, and chronic pelvic pain. RESULTS: To date, there have been multiple off-label reports testing SCS for refractory gastrointestinal and genitourinary conditions. Though some findings have been favorable for these organs and systems, there is insufficient evidence to make this practice routine. The unique configuration and layout of the pelvic pain pathways may not be ideally treated using traditional SCS implantation techniques, and intradural stimulation may be a viable alternative. CONCLUSIONS: Despite the prevalence of visceral pain, the application of neuromodulation therapies, a standard approach for other painful conditions, has received far too little attention, despite promising outcomes from uncontrolled trials. Detailed descriptions of visceral pain pathways may offer several clues that could be used to implement devices tailored to this unique anatomy.

Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling.

The amygdala is a key brain area regulating responses to stress and emotional stimuli, so improving our understanding of how it is regulated could offer novel strategies for treating disturbances in emotion regulation. As we review here, a growing body of evidence indicates that the gut microbiota may contribute to a range of amygdala-dependent brain functions from pain sensitivity to social behavior, emotion regulation, and therefore, psychiatric health. In addition, it appears that the microbiota is necessary for normal development of the amygdala at both the structural and functional levels. While further investigations are needed to elucidate the exact mechanisms of microbiota-to-amygdala communication, ultimately, this work raises the intriguing possibility that the gut microbiota may become a viable treatment target in disorders associated with amygdala dysregulation, including visceral pain, post-traumatic stress disorder, and beyond. Also see the video abstract here: https://youtu.be/O5gvxVJjX18.

A Comprehensive Review of the Celiac Plexus Block for the Management of Chronic Abdominal Pain.

PURPOSE OF REVIEW: Chronic abdominal pain (CAP) is a significant health problem that can dramatically affect quality of life and survival. Pancreatic cancer is recognized as one of the most painful malignancies with 70-80% suffering from substantial pain, often unresponsive to typical medical management. Celiac plexus neurolysis and celiac plexus block (CPB) can be performed to mitigate pain through direct destruction or blockade of visceral afferent nerves. The objective of this manuscript is to provide a comprehensive review of the CPB as it pertains to CAP with a focus on the associated anatomy, indications, techniques, neurolysis/blocking agents, and complications observed in patients who undergo CPB for the treatment of CAP. RECENT FINDINGS: The CAP is difficult to manage due to lack of precision in diagnosis and limited evidence from available treatments. CAP can arise from both benign and malignant causes. Treatment options include pharmacologic, interventional, and biopsychosocial treatments. Opioid therapy is typically utilized for the treatment of CAP; however, opioid therapy is associated with multiple complications. CPB has successfully been used to treat a variety of conditions resulting in CAP. The majority of the literature specifically related to CPB is surrounding chronic pain associated with pancreatic cancer. The literature shows emerging evidence in managing CAP with CPB, specifically in pancreatic cancer. This review provides multiple aspects of CAP and CPB, including anatomy, medical necessity, indications, technical considerations, available evidence, and finally complications related to the management.

Bacterial modulation of visceral sensation: mediators and mechanisms.

The potential role of the intestinal microbiota in modulating visceral pain has received increasing attention during recent years. This has led to the identification of signaling pathways that have been implicated in communication between gut bacteria and peripheral pain pathways. In addition to the well-characterized impact of the microbiota on the immune system, which in turn affects nociceptor excitability, bacteria can modulate visceral afferent pathways by effects on enterocytes, enteroendocrine cells, and the neurons themselves. Proteases produced by bacteria, or by host cells in response to bacteria, can increase or decrease the excitability of nociceptive dorsal root ganglion (DRG) neurons depending on the receptor activated. Short-chain fatty acids generated by colonic bacteria are involved in gut-brain communication, and intracolonic short-chain fatty acids have pronociceptive effects in rodents but may be antinociceptive in humans. Gut bacteria modulate the synthesis and release of enteroendocrine cell mediators, including serotonin and glucagon-like peptide-1, which activate extrinsic afferent neurons. Deciphering the complex interactions between visceral afferent neurons and the gut microbiota may lead to the development of improved probiotic therapies for visceral pain.

Spinal cord stimulation ameliorates detrusor over-activity and visceromotor pain responses in rats with cystitis.

AIM: Interstitial cystitis/painful bladder syndrome/(IC/PBS) results in recurring pain in the bladder and surrounding pelvic region caused by abnormal excitability of micturition reflexes. Spinal cord stimulation (SCS) is currently clinically used for the attenuation of neuropathic and visceral pain. The present study examined whether SCS at upper lumbar segments modulates detrusor overactivity and visceral hyperalgesia associated with cystitis in a rat model of cyclophosphamide (CYP)-induced cystitis. METHODS: Cystitis was induced by intraperitoneal injection of CYP (200 mg/kg) in six adult female Sprague Dawley rats 48 h prior to urodynamic recordings. Another six rats served as-controls with saline injection. Cystometry and the external urethral sphincter (EUS) electromyography during bladder infusion were evaluated under urethane anesthesia. The visceromotor reflexes (VMR) obtained from the external abdominal oblique muscle were quantified during bladder infusion and isotonic bladder distension (IBD), respectively. After baseline recordings were taken, SCS was applied on the dorsal surface of L3 for 25 min. Urodynamic recordings and VMR during bladder infusion and IBD were repeated 2 h after SCS. RESULTS: CYP resulted in detrusor overactivity, stronger EUS tonic contractions, and increased VMR. SCS significantly reduced non-voiding contractions, prolonged EUS relaxation, and delayed VMR appearance during bladder infusion as well as significantly decreased VMR during IBD in cystitis rats. CONCLUSION: SCS improved bladder function and EUS relaxation during bladder infusion and significantly attenuated visceral nociceptive-related VMR during IBD in cystitis rats. SCS may have therapeutic potential for patients with hyperalgesia and IC/PBS.

Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential.

The relationship between gut microbiota and neurological diseases, including chronic pain, has received increasing attention. The gut microbiome is a crucial modulator of visceral pain, whereas recent evidence suggests that gut microbiota may also play a critical role in many other types of chronic pain, including inflammatory pain, headache, neuropathic pain, and opioid tolerance. We present a narrative review of the current understanding on the role of gut microbiota in pain regulation and discuss the possibility of targeting gut microbiota for the management of chronic pain. Numerous signalling molecules derived from gut microbiota, such as by-products of microbiota, metabolites, neurotransmitters, and neuromodulators, act on their receptors and remarkably regulate the peripheral and central sensitisation, which in turn mediate the development of chronic pain. Gut microbiota-derived mediators serve as critical modulators for the induction of peripheral sensitisation, directly or indirectly regulating the excitability of primary nociceptive neurones. In the central nervous system, gut microbiota-derived mediators may regulate neuroinflammation, which involves the activation of cells in the blood-brain barrier, microglia, and infiltrating immune cells, to modulate induction and maintenance of central sensitisation. Thus, we propose that gut microbiota regulates pain in the peripheral and central nervous system, and targeting gut microbiota by diet and pharmabiotic intervention may represent a new therapeutic strategy for the management of chronic pain.

MiR-34a affects dexmedetomidine-inhibited chronic inflammatory visceral pain by targeting to HDAC2.

BACKGROUND: Dexmedetomidine (DEX) has been used as an anesthetic for decades. The present investigation aimed to elucidate the analgesic impact of DEX on 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced chronic inflammatory visceral pain (CIVP) in rats. METHODS: TNBS with or without DEX to Male Sprague-Dawley SD rats were randomly divided into four groups: normal, CIVP, DEX, and vehicle. Pain behaviors were assessed and the abdominal withdrawal reflex, mechanical withdrawal threshold, and thermal withdrawal latency were recorded. Quantitative polymerase chain reaction data showed increased expressions of pro-inflammatory cytokines (IL-6, IL-1ß and TNF-α) in the spinal cord tissues of rats. RESULTS: RNA microarray and quantitative polymerase chain reaction results indicated that miR-34a was downregulated by TNBS induction, but it was upregulated by DEX administration. Further studies showed that transfection of adenovirus-miR-34a inhibitor reversed the effect of DEX on the pain behaviors and spinal-cord pro-inflammatory-cytokine generation in CIVP rats. Additionally, we found that miR-34a targeted the 3'-UTR of the HDAC2 gene, as evinced by the increased HDAC2 expression in the CIVP and DEX + miR-34a inhibitor groups, and decreased HDAC2 signaling in the DEX group. Moreover, knock-down of HDAC2 restored DEX-attenuated pain behaviors and reduced pro-inflammatory cytokine production. CONCLUSIONS: DEX thus exhibited an analgesic effect on CIVP rats through the miR-34a-mediated HDAC2 pathway and suppressed visceral hypersensitivity.

Effect of Transcranial Direct Current Stimulation of the Motor Cortex on Visceral Pain in Patients with Hepatocellular Carcinoma.

Objective: Hepatocellular carcinoma (HCC) is frequently associated with visceral pain. Transcranial direct current stimulation (tDCS) has been proven to reduce chronic pain; however, its effectiveness in malignant visceral pain is unknown. This study aimed to investigate the effects of tDCS in patients with visceral pain due to HCC. Design: This is a randomized, sham-controlled, double-blind, prospective study. Forty patients with visceral pain due to HCC were enrolled and randomly assigned into two groups: a real and a sham group; tDCS was applied over the primary motor area (M1) for 10 consecutive days (2 mA, 30 minutes). Patient's pain was evaluated by visual analog scale (VAS) and verbal descriptor scale (VDS) and for depression by Hamilton rating scale (HAM-D). Evaluation was done at prestimulation, after the first, fifth, and 10th sessions, and one month after the end of stimulation sessions. Results: Real tDCS showed a reduction of VDS (P = 0.001, F = 4.01) and VAS (P = 0.001, F = 6.817) for HAM-D (P = 0.012, F = 5,077); the effect started from the fifth session and continued to one month after stimulation, while in the sham group the effect persisted for five days only. Percentage reduction in all scales in the real group after the 10th session was as follows: VDS P = 0.008, VAS P = 0.001, HAM-D = 0.001; for one month after the end of stimulation, it was as follows: VDS P = 0.001, VAS P = 0.037, HAM-D = 0.002. Conclusions: tDCS proved to be an effective and clinically relevant therapeutic strategy for visceral pain due to HCC.

The Role of the Gastrointestinal Microbiota in Visceral Pain.

A growing body of preclinical and clinical evidence supports a relationship between the complexity and diversity of the microorganisms that inhabit our gut (human gastrointestinal microbiota) and health status. Under normal homeostatic conditions this microbial population helps maintain intestinal peristalsis, mucosal integrity, pH balance, immune priming and protection against invading pathogens. Furthermore, these microbes can influence centrally regulated emotional behaviour through mechanisms including microbially derived bioactive molecules (amino acid metabolites, short-chain fatty acids, neuropeptides and neurotransmitters), mucosal immune and enteroendocrine cell activation, as well as vagal nerve stimulation.The microbiota-gut-brain axis comprises a dynamic matrix of tissues and organs including the brain, autonomic nervous system, glands, gut, immune cells and gastrointestinal microbiota that communicate in a complex multidirectional manner to maintain homeostasis and resist perturbation to the system. Changes to the microbial environment, as a consequence of illness, stress or injury, can lead to a broad spectrum of physiological and behavioural effects locally including a decrease in gut barrier integrity, altered gut motility, inflammatory mediator release as well as nociceptive and distension receptor sensitisation. Centrally mediated events including hypothalamic-pituitary-adrenal (HPA) axis, neuroinflammatory events and neurotransmitter systems are concomitantly altered. Thus, both central and peripheral pathways associated with pain manifestation and perception are altered as a consequence of the microbiota-gut-brain axis imbalance.In this chapter the involvement of the gastrointestinal microbiota in visceral pain is reviewed. We focus on the anatomical and physiological nodes whereby microbiota may be mediating pain response, and address the potential for manipulating gastrointestinal microbiota as a therapeutic target for visceral pain.

A New Method for Sham-Controlled Acupuncture in Experimental Visceral Pain - a Randomized, Single-Blinded Study.

OBJECTIVE: Acupuncture is increasingly used as an alternative to medical therapy for various pain conditions. To study the effect of acupuncture in experimental and clinical studies, a control condition with sham acupuncture is needed. However, as such models have not been established in assessment of acupunctures effect against visceral pain, this study aimed to validate a new method for blinded sham acupuncture in experimental rectal pain. METHODS: Fifteen subjects underwent a sequence of either sham or real acupuncture in randomized order. In the sham arm, a hollow inner tube with a sharp tip was fitted into an outer tube and subjects were blinded to the stimulations. Before and after the intervention, pain was induced by rectal stimulation with an inflatable balloon distended until the subjects' pain threshold was reached. The resting electroencephalogram (EEG) was quantified by spectral power analysis to explore the central nervous system effects objectively. Additionally, after the second study day, the subject was asked to indicate the sequence of interventions. RESULTS: A significant increase in rectal balloon volume was observed after sham 12 ± 21 mL (P = 0.049) and acupuncture 17 ± 30 mL (P = 0.046). However, the change in volume was not different between groups (P = 0.6). No differences in EEG spectral power distributions between sham and acupuncture were seen (all P > 0.6). The correct sequence of sham and acupuncture was indicated by 36% of the subjects (P = 0.4). CONCLUSIONS: The presented sham procedure provides a valid method for blinding of "sham acupuncture" and may be used in future blinded controlled trials of acupuncture for visceral pain.

Animal models of gastrointestinal and liver diseases. Animal models of visceral pain: pathophysiology, translational relevance, and challenges.

Visceral pain describes pain emanating from the thoracic, pelvic, or abdominal organs. In contrast to somatic pain, visceral pain is generally vague, poorly localized, and characterized by hypersensitivity to a stimulus such as organ distension. Animal models have played a pivotal role in our understanding of the mechanisms underlying the pathophysiology of visceral pain. This review focuses on animal models of visceral pain and their translational relevance. In addition, the challenges of using animal models to develop novel therapeutic approaches to treat visceral pain will be discussed.

Effect of electroacupuncture on P2X3 receptor regulation in the peripheral and central nervous systems of rats with visceral pain caused by irritable bowel syndrome.

The aim of this study is to investigate the role of the purinergic receptor P2X3 in the peripheral and central nervous systems during acupuncture treatment for the visceral pain of irritable bowel syndrome (IBS). A total of 24 8-day-old Sprague-Dawley (SD) neonatal male rats (SPF grade) were stimulated using colorectal distention (CRD) when the rats were awake. The modeling lasted for 2 weeks with one stimulation per day. After 6 weeks, the rats were randomly divided into three groups of eight each: (1) the normal group (NG, n = 8); (2) the model group (MG, n = 8); and (3) the model + electroacupuncture group (EA, n = 8) that received electroacupuncture at a needling depth of 5 mm at the Shangjuxu (ST37, bilateral) and Tianshu (ST25, bilateral) acupoints. The parameters of the Han's acupoint nerve stimulator (HANS) were as follows: sparse-dense wave with a frequency of 2/100 Hz, current of 2 mA, 20 min/stimulation, and one stimulation per day; the treatment was provided for seven consecutive days. At the sixth week after the treatment, the abdominal withdrawal reflex (AWR) score was determined; immunofluorescence and immunohistochemistry were used to measure the expression of the P2X3 receptor in myenteric plexus neurons, prefrontal cortex, and anterior cingulate cortex; and, a real-time PCR assay was performed to measure the expression of P2X3 messenger RNA (mRNA) in the dorsal root ganglion (DRG) and spinal cord. After stimulation with CRD, the expression levels of the P2X3 receptor in the inter-colonic myenteric plexus, DRG, spinal cord, prefrontal cortex, and anterior cingulate cortex were upregulated, and the sensitivity of the rats to IBS visceral pain was increased. Electroacupuncture (EA) could downregulate the expression of the P2X3 receptor and ease the sensitivity to visceral pain. The P2X3 receptor plays an important role in IBS visceral pain. The different levels of P2X3 in the peripheral enteric nervous system and central nervous system mediate the effects of the EA treatment of the visceral hyperalgesia of IBS.

[Visceral pain]. / Viszeraler Schmerz.

Chronic visceral pain is an unresolved neurobiological, medical and socioeconomic challenge. Up to 20% of the adult population suffer from chronic visceral pain and abdominal complaints constitute a prevalent symptom also in children and adolescents. Existing treatment approaches are often unsuccessful and patients typically suffer from multiple somatic and psychological symptoms. This complex situation requires integrative treatment approaches. This review summarizes current basic and clinical research on acute and chronic visceral pain with a focus on research groups in Germany. Despite significant clinical and scientific advances, a number of questions remain open calling for more funding to support research to elucidate the complex pathophysiology of chronic visceral pain and to develop and test new treatment approaches. Research support should focus on interdisciplinary concepts and methodology using expertise from multiple disciplines. The field would also benefit from a broader integration of visceral pain into teaching curricula in medicine and psychology and should aim to motivate young clinicians and scientists to strive for a career within this important and highly fascinating area.

Modulation of enteric neurons by interleukin-6 and corticotropin-releasing factor contributes to visceral hypersensitivity and altered colonic motility in a rat model of irritable bowel syndrome.

The search for effective therapeutic strategies for irritable bowel syndrome (IBS) is hampered by an incomplete understanding of its underlying pathophysiology. Stress and altered plasma cytokine profiles indicative of immune activation are characteristic of the disorder. The neuromodulatory effects of interleukin-6 (IL-6) and corticotropin-releasing factor receptor (CRFR) 1 in visceral pain and stress-induced defecation in the Wistar Kyoto (WKY) rat model of IBS were investigated. Sprague Dawley and WKY rats were administered anti-IL-6 receptor antibodies (xIL-6R, 0.5 mg kg(-1) i.p) with or without the CRFR1 antagonist antalarmin (10 mg kg(-1) i.p). Post-intervention, the pain threshold to colorectal distension and stress-induced faecal output were compared and changes in colonic mucosal protein expression were investigated. The neuro-stimulatory effects of IBS plasma on the myenteric plexus is mediated by IL-6, IL-8 and CRF. The stimulatory effects of these soluble factors on myenteric neuron excitability and colonic contractility were additive. Moreover, inhibition of IL-6 and CRF1 receptors in vivo in the WKY IBS rat model normalized stress-induced defecation (P < 0.01) and visceral pain sensitivity (P < 0.001) with associated changes in protein expression of the tight junction proteins occludin and claudin 2, the visceral pain-associated T-type calcium channel CaV3.2 and intracellular signalling molecules STAT3, SOCS3 and ERK1/2. These studies demonstrate the additive effects of immune and stress factors on myenteric neuronal excitability. Moreover, combined targeting of peripheral IL-6 and CRF1 receptors is effective in alleviating IBS-like symptoms in the WKY rat. Thus, crosstalk between stress and immune factors during IBS flares may underlie symptom exacerbation.

Mechanisms of acupuncture-electroacupuncture on persistent pain.

In the last decade, preclinical investigations of electroacupuncture mechanisms on persistent tissue injury (inflammatory), nerve injury (neuropathic), cancer, and visceral pain have increased. These studies show that electroacupuncture activates the nervous system differently in health than in pain conditions, alleviates both sensory and affective inflammatory pain, and inhibits inflammatory and neuropathic pain more effectively at 2 to 10 Hz than at 100 Hz. Electroacupuncture blocks pain by activating a variety of bioactive chemicals through peripheral, spinal, and supraspinal mechanisms. These include opioids, which desensitize peripheral nociceptors and reduce proinflammatory cytokines peripherally and in the spinal cord, and serotonin and norepinephrine, which decrease spinal N-methyl-D-aspartate receptor subunit GluN1 phosphorylation. Additional studies suggest that electroacupuncture, when combined with low dosages of conventional analgesics, provides effective pain management which can forestall the side effects of often-debilitating pharmaceuticals.