Modulation of visceral pain by brain nuclei and brain circuits and the role of acupuncture: a narrative review.

Visceral pain is a complex and heterogeneous pain condition that is often associated with pain-related negative emotional states, including anxiety and depression, and can exert serious effects on a patient's physical and mental health. According to modeling stimulation protocols, the current animal models of visceral pain mainly include the mechanical dilatation model, the ischemic model, and the inflammatory model. Acupuncture can exert analgesic effects by integrating and interacting input signals from acupuncture points and the sites of pain in the central nervous system. The brain nuclei involved in regulating visceral pain mainly include the nucleus of the solitary tract, parabrachial nucleus (PBN), locus coeruleus (LC), rostral ventromedial medulla (RVM), anterior cingulate cortex (ACC), paraventricular nucleus (PVN), and the amygdala. The neural circuits involved are PBN-amygdala, LC-RVM, amygdala-insula, ACC-amygdala, claustrum-ACC, bed nucleus of the stria terminalis-PVN and the PVN-ventral lateral septum circuit. Signals generated by acupuncture can modulate the central structures and interconnected neural circuits of multiple brain regions, including the medulla oblongata, cerebral cortex, thalamus, and hypothalamus. This analgesic process also involves the participation of various neurotransmitters and/or receptors, such as 5-hydroxytryptamine, glutamate, and enkephalin. In addition, acupuncture can regulate visceral pain by influencing functional connections between different brain regions and regulating glucose metabolism. However, there are still some limitations in the research efforts focusing on the specific brain mechanisms associated with the effects of acupuncture on the alleviation of visceral pain. Further animal experiments and clinical studies are now needed to improve our understanding of this area.

Anti-Hyperalgesic Efficacy of Acetyl L-Carnitine (ALCAR) Against Visceral Pain Induced by Colitis: Involvement of Glia in the Enteric and Central Nervous System.

The management of abdominal pain in patients affected by inflammatory bowel diseases (IBDs) still represents a problem because of the lack of effective treatments. Acetyl L-carnitine (ALCAR) has proved useful in the treatment of different types of chronic pain with excellent tolerability. The present work aimed at evaluating the anti-hyperalgesic efficacy of ALCAR in a model of persistent visceral pain associated with colitis induced by 2,4-dinitrobenzene sulfonic acid (DNBS) injection. Two different protocols were applied. In the preventive protocol, ALCAR was administered daily starting 14 days to 24 h before the delivery of DNBS. In the interventive protocol, ALCAR was daily administered starting the same day of DNBS injection, and the treatment was continued for 14 days. In both cases, ALCAR significantly reduced the establishment of visceral hyperalgesia in DNBS-treated animals, though the interventive protocol showed a greater efficacy than the preventive one. The interventive protocol partially reduced colon damage in rats, counteracting enteric glia and spinal astrocyte activation resulting from colitis, as analyzed by immunofluorescence. On the other hand, the preventive protocol effectively protected enteric neurons from the inflammatory insult. These findings suggest the putative usefulness of ALCAR as a food supplement for patients suffering from IBDs.

3, 3'-diindolylmethane enhances macrophage efferocytosis and subsequently relieves visceral pain via the AhR/Nrf2/Arg-1-mediated arginine metabolism pathway.

BACKGROUND: 3, 3'-diindolylmethane (DIM), a classical aryl hydrocarbon receptor (AhR) agonist, has been shown to relieve neuropathic pain, but few studies have reported the efficacy of DIM in visceral pain under colitis condition. PURPOSE: This study aimed to investigate the effect and mechanism of DIM on visceral pain under colitis condition. METHODS: Cytotoxicity was performed using the MTT assay. RT-qPCR and ELISA assays were applied to determine the expression and release of algogenic substance P (SP), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Flow cytometry was used to examine the apoptosis and efferocytosis. The expression of Arg-1-arginine metabolism-related enzymes was detected using western blotting assays. ChIP assays were used to examine the binding of Nrf2 to Arg-1. Mouse models of dextran sulfate sodium (DSS) were established to illustrate the effect of DIM and validate the mechanism in vivo. RESULTS: DIM did not directly affect expressions and release of algogenic SP, NGF and BDNF in enteric glial cells (EGCs). However, when co-cultured with DIM-pre-treated RAW264.7 cells, the release of SP and NGF was decreased in lipopolysaccharides-stimulated EGCs. Furthermore, DIM increased the number of PKH67+ F4/80+ cells in the co-culture system of EGCs and RAW264.7 cells in vitro and alleviated visceral pain under colitis condition by regulating levels of SP and NGF as well as values of electromyogram (EMG), abdominal withdrawal reflex (AWR) and tail-flick latency (TFL) in vivo, which was significantly inhibited by efferocytosis inhibitor. Subsequently, DIM was found to down-regulate levels of intracellular arginine, up-regulate levels of ornithine, putrescine and Arg-1 but not extracellular arginine or other metabolic enzymes, and polyamine scavengers reversed the effect of DIM on efferocytosis and release of SP and NGF. Moving forward, Nrf2 transcription and the binding of Nrf2 to Arg-1-0.7 kb was enhanced by DIM, AhR antagonist CH223191 abolished the promotion of DIM on Arg-1 and efferocytosis. Finally, nor-NOHA validated the importance of Arg-1-dependent arginine metabolism in DIM-alleviated visceral pain. CONCLUSION: DIM enhances macrophage efferocytosis in an arginine metabolism-dependent manner via "AhR-Nrf2/Arg-1" signals and inhibits the release of SP and NGF to relieve visceral pain under colitis condition. These findings provide a potential therapeutic strategy for the treatment of visceral pain in patients with colitis.

Effects of moxibustion on behaviors and tryptophan metabolism-related products in mice with irritable bowel syndrome / 针灸推拿医学（英文版）

Objective: To observe the effect of moxibustion on behaviors and related products of tryptophan (Trp) metabolism in the colon of mice with irritable bowel syndrome (IBS), and to explore the mechanism of moxibustion in the IBS treatment.Methods: Twenty-four mice were randomly divided into a normal group, a model group, a moxibustion group, and a probiotic group, with 6 mice in each group. The visceral pain model of IBS was established by enema with 2,4,6-trinitrobenzene sulfonic acid (TNBS) solution. Mice in the moxibustion group were treated with mild moxibustion at bilateral Zusanli (ST36), and those in the probiotic group were treated with probiotics such as Bifidobacterium by gavage. Abdominal withdrawal reflex (AWR) test, elevated plus-maze (EPM) test, and forced swimming test (FST) were performed after treatment. The expression levels of 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase 1 (TPH1) in the colon were detected by immunofluorescence, and the expression levels of Trp, kynurenine (Kyn), and indole-2,3-oxygenase (IDO) in the colon were detected by enzyme-linked immunosorbent assay. Results: Compared with the normal group, the AWR scores were increased significantly in the model group under different pressure values (P<0.01), the open-arm staying time and open-arm entries in the EPM test were decreased significantly (P<0.01, P<0.05), the motionless time in the FST was increased significantly (P<0.01), and the expression levels of colonic Trp, TPH1, IDO, 5-HT, and Kyn were increased significantly (P<0.01) in the models. Compared with the model group, the AWR scores were differently decreased (P<0.05 or P<0.01), the open-arm entries in the EPM test were increased (P<0.05), the motionless times in the FST were decreased (P<0.05), and the colonic expression levels of Trp, TPH1, IDO, and 5-HT were decreased (P<0.01 or P<0.05) in the moxibustion and probiotic groups; the open-arm staying time was significantly increased in the moxibustion group (P<0.01), and the colonic expression level of Kyn was significantly decreased in the probiotic group (P<0.01). Conclusion: Moxibustion at Zusanli (ST36) improves visceral pain and pain mood and down-regulates the expression levels of colonic TPH1, IDO, Trp, 5-HT, and Kyn in IBS mice.

Folic acid attenuates chronic visceral pain by reducing clostridiales abundance and hydrogen sulfide production.

Irritable bowel syndrome (IBS) related chronic visceral pain affects 20% of people worldwide. The treatment options are very limited. Although the scholarly reviews have appraised the potential effects of the intestinal microbiota on intestinal motility and sensation, the exact mechanism of intestinal microbiota in IBS-like chronic visceral pain remains largely unclear. The purpose of this study is to investigate whether Folic Acid (FA) attenuated visceral pain and its possible mechanisms. Chronic visceral hyperalgesia was induced in rats by neonatal colonic inflammation (NCI). 16S rDNA analysis of fecal samples from human subjects and rats was performed. Patch clamp recording was used to determine synaptic transmission of colonic-related spinal dorsal horn. Alpha diversity of intestinal flora was increased in patients with IBS, as well as the obviously increased abundance of Clostridiales order (a main bacteria producing hydrogen sulfide). The hydrogen sulfide content was positive correlation with visceral pain score in patients with IBS. Consistently, NCI increased Clostridiales frequency and hydrogen sulfide content in feces of adult rats. Notably, the concentration of FA was markedly decreased in peripheral blood of IBS patients compared with non-IBS human subjects. FA supplement alleviated chronic visceral pain and normalized the Clostridiales frequency in NCI rats. In addition, FA supplement significantly reduced the frequency of sEPSCs of neurons in the spinal dorsal horn of NCI rats. Folic Acid treatment attenuated chronic visceral pain of NCI rats through reducing hydrogen sulfide production from Clostridiales in intestine.

Uroprotective and pain-relieving effect of dietary supplementation with micronized palmitoyl-glucosamine and hesperidin in a chronic model of cyclophosphamide-induced cystitis.

Introduction: Feline idiopathic cystitis is a common, chronic-relapsing disorder of the lower urinary tract. In addition to environmental modification/enrichment, long-term and safe treatment targeting specific pathophysiological changes may be of help. In this context, effective dietary interventions hold clinical promise. Palmitoyl-glucosamine (PGA) and hesperidin (HSP) are safe and authorized feed ingredients for animal nutrition under European regulations. Methods: The current study aimed to investigate whether a 3:1 mixture of micronized PGA and HSP could represent a novel mechanism-oriented approach to chronic cystitis management. A newly validated rat model of cyclophosphamide (CYP)-induced chronic cystitis was used (40 mg/kg, three intraperitoneal injections every 3rd day). Animals were randomized to orally receive either vehicle or PGA-HSP at a low (72 + 24 mg/kg) or high (doubled) dose for 13 days, starting 3 days before the chronic CYP protocol, with mesna (2-mercaptoethane-sulfonate) being used as a reference drug. Results: Higher PGA-HSP dose was effective at relieving chronic visceral pain, as measured by mechanical allodynia test (von Frey test). The severity of cystitis was also significantly improved, as shown by the reduced sonographic thickening of the bladder wall, as well as the decrease in edema, bleeding and bladder to body weight ratio compared to the vehicle treated group. A significant decrease of MPO activity, MDA level and fibrosis at Masson's trichrome staining was also observed in animals administered PGA-HSP in comparison to vehicle treated ones. The CYP-induced increase in bladder mRNA expression of pro-inflammatory cytokines was also significantly counteracted by the study mixture. Moreover, CYP-induced bladder mast cell accumulation and releasability were significantly decreased by PGA-HSP (even at the low dose), as determined by metachromatic staining, chymase and tryptase immunostaining as well as enzyme-linked immunosorbent assay for histamine and 5-hydoxytriptamine. Discussion: PGA-HSP is able to block CYP-induced decrease of tight junction proteins, claudin-1 and occludin, thus preserving the urothelial bladder function. Finally, neuroinflammatory changes were investigated, showing that dietary supplementation with PGA-HSP prevented the activation of neurons and non-neuronal cells (i.e., microglia, astrocytes and mast cells) at the spinal level, and counteracted CYP-induced increase of spinal mRNA encoding for pro-inflammatory cytokines. Altogether, the present findings confirm the uroprotective and pain-relieving effect of PGA-HSP and pave the way to potential and relevant clinical applications of the study supplement in feline idiopathic cystitis.

Pharmacological and non-pharmacological therapeutic interventions for the treatment of spinal cord injury-induced pain.

Spinal cord injury (SCI) is a complex neurophysiological disorder, which can result in many long-term complications including changes in mobility, bowel and bladder function, cardiovascular function, and metabolism. In addition, most individuals with SCI experience some form of chronic pain, with one-third of these individuals rating their pain as severe and unrelenting. SCI-induced chronic pain is considered to be "high impact" and broadly affects a number of outcome measures, including daily activity, physical and cognitive function, mood, sleep, and overall quality of life. The majority of SCI pain patients suffer from pain that emanates from regions located below the level of injury. This pain is often rated as the most severe and the underlying mechanisms involve injury-induced plasticity along the entire neuraxis and within the peripheral nervous system. Unfortunately, current therapies for SCI-induced chronic pain lack universal efficacy. Pharmacological treatments, such as opioids, anticonvulsants, and antidepressants, have been shown to have limited success in promoting pain relief. In addition, these treatments are accompanied by many adverse events and safety issues that compound existing functional deficits in the spinally injured, such as gastrointestinal motility and respiration. Non-pharmacological treatments are safer alternatives that can be specifically tailored to the individual and used in tandem with pharmacological therapies if needed. This review describes existing non-pharmacological therapies that have been used to treat SCI-induced pain in both preclinical models and clinical populations. These include physical (i.e., exercise, acupuncture, and hyper- or hypothermia treatments), psychological (i.e., meditation and cognitive behavioral therapy), and dietary interventions (i.e., ketogenic and anti-inflammatory diet). Findings on the effectiveness of these interventions in reducing SCI-induced pain and improving quality of life are discussed. Overall, although studies suggest non-pharmacological treatments could be beneficial in reducing SCI-induced chronic pain, further research is needed. Additionally, because chronic pain, including SCI pain, is complex and has both emotional and physiological components, treatment should be multidisciplinary in nature and ideally tailored specifically to the patient.

The antinociceptive effect of manual acupuncture in the auricular branch of the vagus nerve in visceral and somatic acute pain models and its laterality dependence.

AIMS: The vagus nerve provides an important route to the central nervous system, and its brain projections are involved in nociceptive control and pain perception. We investigated the effect of ABVN stimulation on the inhibition of nociceptive signaling and the role of the cholinergic system in its neurobiological effects in models of visceral-somatic pain in rats, as well as the potential difference in stimulus laterality. MATERIALS AND METHODS: Male and female Wistar rats were pretreated with auricular acupuncture in the ABVN and submitted to the visceral-somatic nociception model by acetic acid or somatic nociception by formalin. Vagotomy and pharmacological tools were used to verify the participation of the cholinergic system in the experiments. KEY FINDINGS: Acupuncture on the left, but not the right, in the ABVN inhibited nociceptive signaling in the visceral-somatic nociception model in male and female rats. Acupuncture on the left ABVN reduced the response time in the formalin test. The cervical vagotomy of the left branch, but not the right, also inhibited nociceptive signaling in the visceral-somatic nociception model and reduced the effect of ABVN stimulation. Furthermore, cholinergic antagonists reduced the left ABVN stimulation effects in the same model. SIGNIFICANCE: Our data show that only the stimulation in the left ABVN is capable of producing antinociceptive effect in acute pain models in rats, and that it is dependent on the activation of the vagus nerve caudal to the nodose ganglion, as well as the muscarinic and nicotinic cholinergic receptors.

Acupuncture relieves the visceral pain of diarrhea-predominant irritable bowel syndrome rats by regulating P2X4 expression.

OBJECTIVES: We researched the effect and mechanism of acupuncture treatment for visceral pain in rats with diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS: We set up a rat model of IBS-D with chemical and chronic- and acute-pressure stimulations. Then, the IBS-D rats were treated with acupuncture or 5-BDBD, and the therapeutic efficacy of acupuncture in IBS-D rats was assessed by means of the Bristol scale, diarrhea index, abdominal withdrawal reflex (AWR) score, mast cell count and histologic staining. RESULTS: Acupuncture significantly decreased clinical symptoms in IBS-D rats after a 14 day-treatment. Furthermore, significant down-regulation of P2X4, OX42, BDNF (brain-derived neurotrophic factor) and IRF-5 (interferon regulatory factor 5) expressions were observed in the IBS-D rats, along with the decreased inflammatory factors [interleukin 1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6)], chemokines [monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), and C-X-C motif chemokine ligand 1 (CXCL1)], and neurotransmitters [substance P (SP), 5-hydroxytryptamine (5-HT), and calcitonin gene-related peptide (CGRP)]. 5-BDBD treatment had a similar effect on IBS-D rats. CONCLUSIONS: Acupuncture can effectively alleviate abdominal pain by decreasing visceral hypersensitivity and controlling the expression of P2X4 and spinal microglial inflammation in IBS rats.

Electroacupuncture Reduces Anxiety Associated With Inflammatory Bowel Disease By Acting on Cannabinoid CB1 Receptors in the Ventral Hippocampus in Mice.

The therapeutic effects of electroacupuncture (EA) on the comorbidity of visceral pain and anxiety in patients with inflammatory bowel disease (IBD) is well known. It has been known that the ventral hippocampus (vHPC) and the cannabinoid type 1 receptors (CB1R) are involved in regulating anxiety and pain. Therefore, in this study, we determined whether EA reduces visceral pain and IBD-induced anxiety via CB1R in the vHPC. We found that EA alleviated visceral hyperalgesia and anxiety in TNBS-treated IBD mice. EA reversed over-expression of CB1R in IBD mice and decreased the percentage of CB1R-expressed GABAergic neurons in the vHPC. Ablating CB1R of GABAergic neurons in the vHPC alleviated anxiety in TNBS-treated mice and mimicked the anxiolytic effect of EA. While ablating CB1R in glutamatergic neurons in the vHPC induced severe anxiety in wild type mice and inhibited the anxiolytic effect of EA. However, ablating CB1R in either GABAergic or glutamatergic neurons in the vHPC did not alter visceral pain. In conclusion, we found CB1R in both GABAergic neurons and glutamatergic neurons are involved in the inhibitory effect of EA on anxiety but not visceral pain in IBD mice. EA may exert anxiolytic effect via downregulating CB1R in GABAergic neurons and activating CB1R in glutamatergic neurons in the vHPC, thus reducing the release of glutamate and inhibiting the anxiety circuit related to vHPC. Thus, our study provides new information about the cellular and molecular mechanisms of the therapeutic effect of EA on anxiety induced by IBD.

Gallic Acid Alleviates Visceral Pain and Depression via Inhibition of P2X7 Receptor.

Chronic visceral pain can occur in many disorders, the most common of which is irritable bowel syndrome (IBS). Moreover, depression is a frequent comorbidity of chronic visceral pain. The P2X7 receptor is crucial in inflammatory processes and is closely connected to developing pain and depression. Gallic acid, a phenolic acid that can be extracted from traditional Chinese medicine, has been demonstrated to be anti-inflammatory and anti-depressive. In this study, we investigated whether gallic acid could alleviate comorbid visceral pain and depression by reducing the expression of the P2X7 receptor. To this end, the pain thresholds of rats with comorbid visceral pain and depression were gauged using the abdominal withdraw reflex score, whereas the depression level of each rat was quantified using the sucrose preference test, the forced swimming test, and the open field test. The expressions of the P2X7 receptor in the hippocampus, spinal cord, and dorsal root ganglion (DRG) were assessed by Western blotting and quantitative real-time PCR. Furthermore, the distributions of the P2X7 receptor and glial fibrillary acidic protein (GFAP) in the hippocampus and DRG were investigated in immunofluorescent experiments. The expressions of p-ERK1/2 and ERK1/2 were determined using Western blotting. The enzyme-linked immunosorbent assay was utilized to measure the concentrations of IL-1ß, TNF-α, and IL-10 in the serum. Our results demonstrate that gallic acid was able to alleviate both pain and depression in the rats under study. Gallic acid also reduced the expressions of the P2X7 receptor and p-ERK1/2 in the hippocampi, spinal cords, and DRGs of these rats. Moreover, gallic acid treatment decreased the serum concentrations of IL-1ß and TNF-α, while raising IL-10 levels in these rats. Thus, gallic acid may be an effective novel candidate for the treatment of comorbid visceral pain and depression by inhibiting the expressions of the P2X7 receptor in the hippocampus, spinal cord, and DRG.

Electroacupuncture Reduces Visceral Pain Via Cannabinoid CB2 Receptors in a Mouse Model of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) results in chronic abdominal pain in patients due to the presence of inflammatory responses in the colon. Electroacupuncture (EA) is effective in alleviating visceral pain and colonic inflammation associated with IBD. Cannabinoid CB2 receptor agonists also reduce colonic inflammation in a mouse model of IBD. However, whether EA reduces visceral pain and colonic inflammation via the CB2 receptor remains unknown. Here, we determined the mechanism of the antinociceptive effect of EA in a mouse model of IBD induced by rectal perfusion of 2,4,6-trinitrobenzenesulfonic acid solution (TNBS). EA or sham EA was performed at the bilateral Dachangshu (BL25) point for seven consecutive days. The von Frey and colorectal distension tests were performed to measure mechanical referred pain and visceral pain. Western blotting and immunohistochemistry assays were carried out to determine the expression of IL-1ß and iNOS and activation of macrophages in the colon tissues. We found that EA, but not sham EA, attenuated visceral hypersensitivity and promoted activation of CB2 receptors, which in turn inhibited macrophage activation and the expression of IL-1ß and iNOS. The effects of EA were blocked by AM630, a specific CB2 receptor antagonist, and by CB2 receptor knockout. Our findings suggest that EA attenuates mechanical allodynia and visceral hypersensitivity associated with IBD by activating CB2 receptors and subsequent inhibition of macrophage activation and expression of IL-1ß and iNOS.

Gentians, natural remedies for future of visceral pain control; an ethnopharmacological review with an in silico approach.

Different gentian preparations are used as traditional remedies for internal pain control in: Persian traditional medicine (PTM), Chinese traditional medicine (CTM) and Ancient Greek medicine (AGM) from the time of the Roman Empire. Objective: To present a survey of the ethnopharmacological applications of gentians recorded as being used in Eastern and Western traditional medical systems (PTM, CTM and AGM) and their pharmacological effects, chemical composition as well as an in silico investigation of the possible active component/s for the alleviation of internal pain via molecular docking studies. Major traditional medicine literature (PTM, CTM and AGM, 50 AD- 1770) and ethnobotanical studies for the application of gentians were reviewed. Nine European species representing 5 of the 13 sections currently attributed to Gentiana were selected. Chemical compounds and pharmacological activity data of these species were gathered from different databases including Google Scholar, PubChem, PubMed and Web of Science (between 1972 and 2020). The possible active constituents of gentians on visceral pain receptors were investigated, in silico. In all investigated literature, traditional uses of gentian were indicated to have anti-nociceptive effects on visceral pain and possess diuretic action. According to our computational study, acylated flavonoid glycosides, viz. trans-feruloyl-2"-isovitexin (33), trans-feruloyl-2"-isovitexin-4'-O-ß-D-glucoside (34), iso-orientin-4'-O-glucoside (38), trans-caffeoyl-2"-iso-orientin-4'-O-ß-D-glucoside (39), iso-orientin-2"-O-ß-D-glucoside (40) and isoscoparin (41), might be responsible for visceral pain reduction by interacting with the purinergic receptor (P2X3) and vanilloid receptor 1 (TrpV1). This finding shows a good correlation with different traditional gentian uses in Persian, Chinese and European ethnomedicine for visceral pain control.

Supplementation with milk fat globule membrane from early life reduces maternal separation-induced visceral pain independent of enteric nervous system or intestinal permeability changes in the rat.

Nutritional approaches have emerged over the past number of years as suitable interventions to ameliorate the enduring effects of early life stress. Maternal separation (MS) is a rodent model of early life stress which induces widespread changes across the microbiota-gut-brain axis. Milk fat globule membrane (MFGM) is a neuroactive membrane structure that surrounds milk fat globules in breast milk and has been shown to have positive health effects in infants, yet mechanisms behind this are not fully known. Here, we investigated the effects of MFGM supplementation from birth on a variety of gut-brain signalling pathways in MS and non-separated control animals across the lifespan. Specifically, visceral sensitivity as well as spatial and recognition memory were assessed in adulthood, while gut barrier permeability, enteric nervous system (ENS) and glial network structure were evaluated in both early life and adulthood. MS resulted in visceral hypersensitivity, which was ameliorated to a greater extent by supplementation with MFGM from birth. Modest effects of both MS and dietary supplementation were noted on spatial memory. No effects of MS were observed on enteric neuronal or glial networks in early life or adulthood, however an increase in the immunoreactivity of ßIII-tubulin in adult colonic myenteric ganglia was noted in the MFGM intervention non-separated group. In conclusion, dietary supplementation with MFGM from birth is sufficient to block MS-induced visceral hypersensitivity, highlighting its potential value in visceral pain-associated disorders, but future studies are required to fully elucidate the mechanistic role of this supplementation on MS-induced visceral pain.

Impaired visceral pain-related functions of the midbrain periaqueductal gray in rats with colitis.

The midbrain periaqueductal gray (PAG) is a key structure involved in the supraspinal modulation of pain. Previous studies have reported the association of gut inflammation-triggered chronic abdominal pain with structural and neuronal alterations within the PAG. However, whether PAG-executed visceral nociception processing and descending modulation are altered in gut pathology is not known. We used c-Fos immunohistochemistry and extracellular microelectrode recording in urethane-anesthetized male Wistar rats to evaluate the colitis-induced changes in visceral pain-related neuronal properties of the PAG and its descending outflow to visceral nociceptive neurons of the caudal ventrolateral medulla (CVLM). Analysis of c-Fos protein expression in inflamed animals has shown diminished activation of the lateral and ventrolateral PAG columns by noxious colorectal distension (CRD), although the nonstimulated c-Fos labeling in these PAG subdivisions was enhanced compared with that in controls. Microelectrode recording in the ventrolateral PAG revealed a colitis-elicited decrease in the proportion of CRD-excited neurons accompanied by an increase in the number of unresponsive cells and weakened reactions to the stimulation of CRD-inhibited PAG units. Colonic inflammation has also been found to cause a shift in the effects of ventrolateral PAG electrostimulation on CRD-excited CVLM neurons from being mostly inhibitory under normal conditions to excitatory in colitis. These findings identify impaired PAG functioning in ascending and descending visceral nociception control that may contribute to gut injury-associated visceral hyperalgesia. The data obtained can benefit a better understanding of the supraspinal mechanisms involved in the pathogenesis of postinflammatory chronic abdominal pain.

Maigne Syndrome - A potentially treatable yet underdiagnosed cause of low back pain: A review.

BACKGROUND: First discussed by Dr. Robert Maigne in the late 1980s, Maigne Syndrome is an often unrecognized and treatable cause of low back pain. It can be separated into two distinct entities. The central variant is a result of nerve afferent input secondary to changes of facet joint arthropathy at the thoracolumbar junction. The peripheral variant is a result of impingement of the medial branch of the superior cluneal nerve, which arises from the posterior rami of the lower thoracic and upper lumbar nerve roots, and results in similar clinical symptoms and signs. OBJECTIVE: To review the current literature for a comprehensive description of Maigne Syndrome, its diagnosis and management. METHODS: Evidence was gathered using two main medical databases, namely PubMed and Google Scholar. Search terms included 'Maigne's Syndrome', 'Maigne facet', 'thoracolumbar junction syndrome', 'cluneal nerve entrapment', 'posterior iliac crest trigger point', 'pseudosciatica', as well as various permutations of these terms. RESULTS: The initial search generated 52 articles. These were screened, and duplicate and irrelevant articles were removed. Using the remaining articles, and with evaluation of their cited references, we selected 28 articles for review. Most of these consisted of case reports, many of which were published in rehabilitation, chiropractic and medical journals. The papers explored topics such as anatomy, cluneal nerve imaging, and treatment of nerve entrapment and facet related back pain syndromes, and have been included in this review, which is, to the best our knowledge, the most comprehensive description of Maigne Syndrome to date. CONCLUSION: The keys to the diagnosis of Maigne Syndrome include an awareness of the mechanical causes of back dominant pain, an understanding of the relevant anatomy, a specific clinical examination, and focused radiological guided anesthetic blocks. Treatment is available, and as in all back-pain etiologies, is most effective in the early stages of the disease.

P2Y12 receptor as a new target for electroacupuncture relieving comorbidity of visceral pain and depression of inflammatory bowel disease.

BACKGROUND: The P2Y12 receptor is a kind of purinoceptor that is engaged in platelet aggregation, and P2Y12 inhibitors have been used in clinical antithrombotic therapy. The P2Y12 receptor in microglia induces interleukin-1ß (IL-1ß) expression, which is a key mediator of depression in the brain. Although peripheral P2Y12 is involved in neuropathic pain, whether P2Y12 expression in the medial prefrontal cortex (mPFC) is associated with comorbidities of visceral pain and depression remains unclear. Accumulating evidence suggests that electroacupuncture (EA) is effective in treating inflammatory bowel disease (IBD), but its mechanism is unknown. This study aimed to determine whether P2Y12 expression in the mPFC is associated with comorbidities of visceral pain and depression in IBD and whether EA treats IBD by targeting the P2Y12 receptor. METHODS: We used 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced IBD mice. P2Y12 short hairpin RNA (shRNA) was stereotaxically injected into the bilateral mPFC. EA was performed on bilateral "Dachangshu" (BL25) acupoints once a day for 7 days. Von Frey filaments and colorectal distension were used to detect the mechanical pain threshold and visceral pain sensitivity. The sucrose preference test, tail suspension test and forced swimming test were used to evaluate depression in mice. Western blotting was used to test the expression of P2Y12 and IL-1ß. Immunofluorescence staining was used to assess microglial activity. RESULTS: We found that IBD mice presented visceral pain and depression associated with increased P2Y12 expression in the mPFC. P2Y12 shRNA significantly attenuated visceral pain and depression in IBD mice. P2Y12 shRNA significantly downregulated IL-1ß expression and inhibited the activation of microglia in the mPFC of IBD mice. Meanwhile, EA played a similar role of P2Y12 shRNA. EA significantly downregulated P2Y12 expression, weakened the activation of microglia, and then inhibited IL-1ß expression in the mPFC, thus relieving visceral pain and depression in IBD mice. CONCLUSION: The present study provided new ideas that the P2Y12 receptor in the mPFC could be a new target for the treatment of comorbid visceral pain and depression by EA. This may not only deepen our understanding of the analgesic and antidepressant mechanisms of EA but also promote the application of EA to treat IBD.

Neuromodulation in Treating Pelvic Pain.

PURPOSE OF REVIEW: Chronic pelvic pain (CPP) is a complex condition that can be multifactorial, disabling, and difficult to treat. It is important to understand the various diagnoses and pathways that can be involved and have an understanding of the available treatment options. RECENT FINDINGS: There is a complex innervation of the pelvic region which makes its treatment very challenging. There are pathophysiological similarities of CPP to disease states like complex regional pain syndrome and sympathetically driven pain. CPP is poorly understood and includes psychological, psychosocial, cultural, and economic influences. Treatment options vary, but neuromodulation does remain a centerpiece and can include sacral stimulation, SCS, DRG stimulation, and PNS.

Regulatory effect of mild moxibustion on P2X3 receptors in spinal cord, anterior cingulate cortex and thalamic ventral posterolateral nucleus of rats with IBS visceral hyperalgesia / 针灸推拿医学（英文版）

Objective: To observe the therapeutic effect of mild moxibustion on irritable bowel syndrome (IBS) visceral hyperalgesiamodel rats and its regulatory effect on P2X3 receptors in the spinal cord, anterior cingutate cortex (ACC) and thalamic ventral posterolateral nucleus (VPL). Methods: Thirty 8-day-old newborn rats were randomly divided into a normal group (n=6) and a modeling group (n=24) according to the completely random number table method. Rats in the normal group were bred routinely, and those in the modeling group were subjected to preparing IBS chronic visceral hyperalgesia model using colorectal distention (CRD) in stimulation method. Rats successfully modelled were re-divided into a model group, a mild moxibustion group, a P2X3 receptor antagonist group, and a normal saline group according to the completely random number table method with 6 rats in each group. Rats in each group received corresponding interventions from the 37-day old, once a day for 7 consecutive days. Immunohistochemistry and Western blot assays were used to detect P2X3 protein expressions in the spinal cord, ACC and VPL of rats. Results: Under different intensities of CRD stimulation, the abdominal withdrawal reflex (AWR) scores of the model group were significantly increased versus the normal group (all P<0.05); the AWR scores of the mild moxibustion group and the P2X3 receptor antagonist group were significantly reduced versus the model group (all P<0.01). The P2X3 protein expressions in rat spinal cord, ACC and VPL tissues of the model group were significantly increased versus the normal group (all P<0.01); the P2X3 protein expressions in rat spinal cord, ACC and VPL tissues of the mild moxibustion group and the P2X3 receptor antagonist group were significantly reduced versus the model group (all P<0.01). Conclusion: Mild moxibustion can inhibit the P2X3 receptor expressions in the spinal cord, ACC, and VPL tissues of IBS visceral hyperalgesia model rats, which may be the mechanism of mild moxibustion in relieving the central sensitization of rats with IBS visceral hyperalgesia.

Pharmacologycal activity of peperina (Minthostachys verticillata) on gastrointestinal tract.

ETHNOPHARMACOLOGICAL RELEVANCE: Minthostachys verticillata (Griseb.) Epling (Lamiaceae), known as Peperina is a medicinal native plant, with a traditional use as a digestive, antispasmodic and antidiarrheic. AIM OF THE STUDY: Despite its folkloric use, no scientific evaluation of this plant related to the gastrointestinal inflammatory process has been carried out to date. The present study aims to assess the effects of M. verticillata on gastrointestinal system in experimental models. MATERIALS AND METHODS: M. verticillata (250 and 500 mg/kg) was orally tested in a colitis model induced by acetic acid. Colon weight/length ratio, oxidative stress (oxidized and reduced glutathione), histological changes using Alcian blue and hematoxylin & eosin staining and expression of IL1ß, TNFα, iNOS, COX-2 were evaluated. The effect of the extract in three additional in vivo models were studied: intestinal motility and diarrhea induced by ricin oil, and visceral pain induced by intracolonic administration of capsaicin. Finally, the activity on concentration response curves of acetylcholine, calcium chloride, potassium and serotonin were achieved in isolated rat jejunum. RESULTS: In the colitis model, M. verticillata induced a significant reduction in the colon weight/length ratio, oxidative stress and expression levels of IL-1ß, iNOS and COX-2. Also, the extract diminished the severity of microscopic tissue damage and showed protective effect on goblet cells. Intestinal motility, diarrhea, visceral pain-related behaviors and referred hyperalgesia were significantly reduced when the animals were treated with the extract. Furthermore, in isolated jejunum, M. verticillata significantly reduced the contraction induced by serotonin and acetylcholine. Likewise, the extract non-competitively inhibited the response-concentration induced by CaCl2 and inhibited both low and high K+-induced contractions. CONCLUSIONS: This is the first study to validate traditional use of M. verticillata for digestive disorders and demonstrated that its aqueous extract could represent a promising strategy in targeting the multifactorial pathophysiology of inflammatory bowel disease.