Effect of Preemptive Ketamine Administration on Postoperative Visceral Pain after Gynecological Laparoscopic Surgery

The pain following gynecological laparoscopic surgery is less intense than that following open surgery; however, patients often experience visceral pain after the former surgery. The aim of this study was to determine the effects of preemptive ketamine on visceral pain in patients undergoing gynecological laparoscopic surgery. Ninety patients undergoing gynecological laparoscopic surgery were randomly assigned to one of three groups. Group 1 received placebo. Group 2 was intravenously injected with preincisional saline and local infiltration with 20 m L ropivacaine（4 mg/m L） at the end of surgery. Group 3 was intravenously injected with preincisional ketamine（0.3 mg/kg） and local infiltration with 20 m L ropivacaine（4 mg/m L） at the end of surgery. A standard anesthetic was used for all patients, and meperidine was used for postoperative analgesia. The visual analogue scale（VAS） scores for incisional and visceral pain at 2, 6, 12, and 24 h, cumulative analgesic consumption and time until first analgesic medication request, and adverse effects were recorded postoperatively. The VAS scores of visceral pain in group 3 were significantly lower than those in group 2 and group 1 at 2 h and 6 h postoperatively（P〈0.05 and P〈0.01, respectively）. At 2 h and 6 h, the VAS scores of incisional pain did not differ significantly between groups 2 and 3, but they were significantly lower than those in group 1（P〈0.01）. Groups 1 and 2 did not show any differences in visceral pain scores at 2 h and 6 h postoperatively. Moreover, the three groups showed no statistically significant differences in visceral and incisional pain scores at 12 h and 24 h postoperatively. The consumption of analgesics was significantly greater in group 1 than in groups 2 and 3, and the time to first request for analgesics was significantly longer in groups 2 and 3 than in group 1, with no statistically significant difference between groups 2 and 3. However, the three groups showed no significant difference in the incidence of shoulder pain or adverse effects. Preemptive ketamine may reduce visceral pain in patients undergoing gynecological laparoscopic surgery.

Estrogen augmented visceral pain and colonic neuron modulation in a double-hit model of prenatal and adult stress

BACKGROUND Chronic stress during pregnancy may increase visceral hyperalgesia of offspring in a sex-dependent way.Combining adult stress in offspring will increase this sensitivity.Based on the evidence implicating estrogen in exacerbating visceral hypersensitivity in female rodents in preclinical models,we predicted that chronic prenatal stress(CPS)+chronic adult stress(CAS)will maximize visceral hyperalgesia;and that estrogen plays an important role in colonic hyperalgesia.AIM The aim was to illuminate the role of estrogen in colonic hyperalgesia and its underlying mechanisms.METHODS We established a CPS plus CAS rodent model in which the balloon was used to distend the colorectum.The single-fiber recording in vivo and patch clamp experiments in vitro were used to monitor the colonic neuron’s activity.The reverse transcription-polymerase chain reaction,western blot,and immunofluorescence were used to study the effects of CPS and CAS on colon primary afferent sensitivity.We used ovariectomy and letrozole to reduce estrogen levels of female rats respectively in order to assess the role of estrogen in female-specific enhanced primary afferent sensitization.RESULTS Spontaneous activity and single fiber activity were significantly greater in females than in males.The enhanced sensitization in female rats mainly came from lowthreshold neurons.CPS significantly increased single-unit afferent fiber activity in L6-S2 dorsal roots in response.Activity was further enhanced by CAS.In addition,the excitability of colon-projecting dorsal root ganglion(DRG)neurons increased in CPS+CAS rats and was associated with a decrease in transient Atype K+currents.Compared with ovariectomy,treatment with the aromatase inhibitor letrozole significantly reduced estrogen levels in female rats,confirming the gender difference.Moreover,mice treated with letrozole had decreased colonic DRG neuron excitability.The intrathecal infusion of estrogen increased brain-derived neurotrophic factor(BDNF)protein levels and contributed to the response to visceral pain.Western blotting showed that nerve growth factor protein was upregulated in CPS+CAS mice.CONCLUSION This study adds to the evidence that estrogen-dependent sensitization of primary afferent colon neurons is involved in the development of chronic stress-induced visceral hypersensitivity in female rats.

Possible implications of animal models for the assessment of visceral pain

Acute pain,provoked generally after the activation of peripheral nociceptors,is an adaptive sensory function that alerts the individual to avoid noxious stimuli.However,uncontrolled acute pain has a maladaptive role in sensory activity leading to development of a chronic pain state which persists even after the damage is resolved,or in some cases,in the absence of an initial local acute injury.Huge numbers of people suffer from visceral pain at least once during their life span,leading to substantial health care costs.Although studies reporting on the mechanism of visceral pain are accumulating,it is still not precisely understood.Therefore,this review aims to elucidate the mechanism of visceral pain through an evaluation of different animal models and their application to develop novel therapeutic approaches for treating visceral pain.To assess the nociceptive responses in viscera,several visceral pain models such as inflammatory,traction,stress and genetic models utilizing different methods of measurement have been devised.Among them,the inflammatory and traction models are widely used for studying the visceral pain mechanism of different disease conditions and post-operative surgery in humans and animals.A hapten,2,4,6-trinitrobenzene sulfonic acid(TNBS),has been extensively used as an inflammatory agent to induce visceral pain.The traction model seems to cause a strong pain stimulation and autonomic reaction and could thus be the most appropriate model for studying the underlying visceral pain mechanism and for probing the therapeutic efficacies of various anesthetic and analgesics for the treatment of visceral pain and hyperalgesia.

Acupuncture and moxibustion for visceral pain

Totally three articles focusing on"analgesic action of suspended moxibustion effect in visceral hypersensitivity rats with irritable bowel syndrome,and changes in prokineticin 1 and prokineticin receptor 1 expression in the spinal cord,enkephalins in the spinal cord and prokineticin-1 and prokineticin receptor-1 in the colon tissue during the analgesic progress"were

Electroacupuncture Attenuates Visceral Pain and Reverses Upregulation of TRPV1 Expression in Adult Rats with Neonatal Maternal Deprivation

Irritable bowel syndrome (IBS) is characterized by chronic visceral hypersensitivity that companied by altered bowel movement. However, the treatment options are very limited. The aim of this study was to investigate effects of electroacupuncture (EA) on visceral hypersensitivity in a rat model of IBS and to explore the underlying mechanisms of EA effects. Visceral hypersensitivity was established by neonatal maternal deprivation (NMD) in male rats on postnatal days 2 - 15. Behavioral experiments were conducted at the age of 7 weeks. Treatment with EA at Zusanli (stomach-36, ST-36) significantly reduced abdominal withdrawal reflex (AWR) scores in NMD rats but not in age-matched healthy control rats. In addition, EA treatment hyperpolarized resting membrane potentials, increased the rheobase and reduced the numbers of action potentials evoked by 2 and 3 times rheobase current stimulation of dorsal root ganglion (DRG) neurons innervating the colon. NMD markedly enhanced expression of TRPV1 in colon related DRGs while EA treatment drastically suppressed the expression of TRPV1 in DRGs of NMD rats. These data suggest that EA treatment produced an analgesic effect, which might be mediated at least in a part by suppression of TRPV1 expression and by inhibition of neuronal excitability of primary sensory neurons in rats with chronic visceral pain.

Effect of pre-electroacupuncture on p38 and c-Fos expression in the spinal dorsal horn of rats suffering from visceral pain

Background Acupuncture is an effective way to relieve pain, but the mechanism by which electroacupuncture （EA） decreases the visceral pain state still remains unclear. This study aimed to evaluate the effects of pre-electroacupuncture on pain behaviors, p38 phosphorylation, and c-Fos protein and mRNA expression in both the colonic wall and spinal dorsal horn of rats suffering from visceral pain. This study also investigated the probable signaling regulatory mechanism of the analgesic effect induced by electroacupuncture. Methods All rats were randomized into the control （Con） group, the Con＋EA group, the visceral pain （VP） group, and VP＋EA group （n=8 for all groups）. The visceral pain model was established using 40 ul of 5% formalin solution injected into the colon of rats. EA was applied to the bilateral Jiaji acupoints for 20 minutes before application of visceral pain. Parameters for EA were set at a continuous wave （20 Hz） and intensity where the rats shook their whiskers but did not scrabble （≤1 mA）. The visceral pain score was recorded and the expressions of p38 and c-Fos protein were detected using Western blotting. Real-time quantitative PCR was also used to determine the expression of c-Fos mRNA. Results Rats in the VP group immediately presented with obvious visceral pain behaviors after being injected with formalin. p38 activity and c-Fos protein and mRNA expression in both the colonic wall and spinal dorsal horn were higher in the VP group than in the Con group （P 〈0.05）. By contrast, visceral pain behaviors were delayed in rats from the VP＋EA group. p38 activity and c-Fos protein and mRNA expression were lower in the VP＋EA group than that in the VP group （P〈0.01）. Conclusions Pre-electroacupuncture of the Jiaji acupoint has prophylactic analgesic effects on rats suffering from visceral pain. The p38 signal transduction pathway may be partly involved in the regulatory mechanism of this analgesic effect.

The role of cyclooxygenase-2/prostanoid pathway in visceral pain induced liver stress response in rats

Background Cyclooxygenase （COX） is the rate-limiting enzyme in the production of prostanoids from arachidonic acid. COX-2 is the inducible enzyme in the COX family, together with the prostanoids forms the COX-2/prostanoid pathway. Research showed that the COX-2/prostanoid pathway is activated in hepatic diseases and liver stress reaction, such as fibrogenesis, portal hypertension, carcinogenesis, and ischemic/repeffusion injury. But there was no report on visceral pain induced liver stress. This study was to investigate the role of the COX-2/prostanoid pathway in liver stress response in rat acute colitis visceral pain liver stress model.Methods Fifty-three male SD rats were randomly divided into Naive, Model, NS398 treatment, and Morphine treatment groups. The rat acute colitis visceral pain liver stress model was established under anesthesia by the colonic administration of 0.5 ml of 6% acetic acid using a urethral catheter. NS398 and morphine were administrated 30 minutes prior to model establishment in NS398 and Morphine treatment groups respectively. Spontaneous activities and pain behavior were counted and the extent of colonic inflammation was assessed histologically. Liver tissue levels of Glutathione-S-Transferase （GST） activity, COX-2 mRNA, prostaglandin E2 （PGE2）, thromboxane B2 （TXB2） and 6-Ketone-prostaglandin F1α （6-K-PGF1α） contents were assessed.Results Thirty minutes after the colonic administration of acetic acid, a significant decrease in spontaneous activities and an increase in pain behaviors were observed in Model group （P〈0.01 and P〈0.05 respectively）, accompanied by colonic inflammation. Liver GST activity levels significantly dropped （P〈0.05）. Liver COX-2 mRNA expressi.on significantly increased, accompanied by an increase in liver concentrations of PGE2 and TXB2, but no obvious change in 6-K-PGF1α concentrations. NS398 and morphine both ameliorated post-stress liver GST activity （P〈0.05 and P〈0.01 respectively）, decreased stress-induced COX-2 expression, decreased PGE2 and TXB2 production, but increased liver 6-K-PGF1α levels. Morphine attenuation in colonic tissue inflammation was apparent at 24 hours （P〈0.05）.Conclusions Acute colitis visceral pain liver stress can induce liver injury. Liver injury might have occurred through the activation of the COX-2/prostanoid pathway and increased production of PGE2 and TXB2. Effective analgesia might offer protective effect during visceral pain stress.

Anterior herniation of lumbar disc induces persistent visceral pain： discogenic visceral pain

Background Visceral pain is a common cause for seeking medical attention. Afferent fibers innervating viscera project to the central nervous system via sympathetic nerves. The lumbar sympathetic nerve trunk lies in front of the lumbar spine. Thus, it is possible for patients to suffer visceral pain originating from sympathetic nerve irritation induced by anterior herniation of the lumbar disc. This study aimed to evaluate lumbar discogenic visceral pain and its treatment. Methods Twelve consecutive patients with a median age of 56.4 years were enrolled for investigation between June 2012 and December 2012. These patients suffered from long-term abdominal pain unresponsive to current treatment options. Apart from obvious anterior herniation of the lumbar discs and high signal intensity anterior to the herniated disc on magnetic resonance imaging, no significant pathology was noted on gastroscopy, vascular ultrasound, or abdominal computed tomography （CT）. To prove that their visceral pain originated from the anteriorly protruding disc, we evaluated whether pain was relieved by sympathetic block at the level of the anteriorly protruding disc. If the block was effective, CT-guided continuous lumbar sympathetic nerve block was finally performed. Results All patients were positive for pain relief by sympathetic block. Furthermore, the average Visual Analog Scale of visceral pain significantly improved after treatment in all patients （P 〈0.05）. Up to 11/12 patients had satisfactory pain relief at 1 week after discharge, 8/12 at 4 weeks, 7/12 at 8 weeks, 6/12 at 12 weeks, and 5/12 at 24 weeks. Conclusions It is important to consider the possibility of discogenic visceral pain secondary to anterior herniation of the lumbar disc when forming a differential diagnosis for seemingly idiopathic abdominal pain. Continuous lumbar sympathetic nerve block is an effective and safe therapy for patients with discogenic visceral pain.

Targeting GATA1 and p2x7r Locus Binding in Spinal Astrocytes Suppresses Chronic Visceral Pain by Promoting DNA Demethylation

Irritable bowel syndrome is a gastrointestinal disorder of unknown etiology characterized by widespread,chronic abdominal pain associated with altered bowel movements.Increasing amounts of evidence indicate that injury and inflammation during the neonatal period have long-term effects on tissue structure and function in the adult that may predispose to gastrointestinal diseases.In this study we aimed to investigate how the epigenetic regulation of DNA demethylation of the p2x7r locus guided by the transcription factor GATA binding protein 1(GATA1)in spinal astrocytes affects chronic visceral pain in adult rats with neonatal colonic inflammation(NCI).The spinal GATA1 targeting to DNA demethylation of p2x7r locus in these rats was assessed by assessing GATA1 function with luciferase assay,chromatin immunoprecipitation,patch clamp,and interference in vitro and in vivo.In addition,a decoy oligodeoxynucleotide was designed and applied to determine the influence of GATA1 on the DNA methylation of a p2x7r CpG island.We showed that NCI caused the induction of GATA1,Ten-eleven translocation 3(TET3),and purinergic receptors(P2X7Rs)in astrocytes of the spinal dorsal horn,and demonstrated that inhibiting these molecules markedly increased the pain threshold,inhibited the activation of astrocytes,and decreased the spinal sEPSC frequency.NCI also markedly demethylated the p2x7r locus in a manner dependent on the enhancement of both a GATA1–TET3 physical interaction and GATA1 binding at the p2x7r promoter.Importantly,we showed that demethylation of the p2x7r locus(and the attendant increase in P2X7R expression)was reversed upon knockdown of GATA1 or TET3 expression,and demonstrated that a decoy oligodeoxynucleotide that selectively blocked the GATA1 binding site increased the methylation of a CpG island in the p2x7r promoter.These results demonstrate that chronic visceral pain is mediated synergistically by GATA1 and TET3 via a DNA-demethylation mechanism that controls p2x7r transcription in spinal dorsal horn astrocytes,and provide a potential therapeutic strategy by targeting GATA1 and p2x7r locus binding.

Pretreatment of emulational manual acupuncture versus electroacupuncture against visceral traction pain in rats

BACKGROUND： Acupuncture and moxibustion against visceral noxious stimulation present different mechanisms in the peripheral and central nervous systems, involving release of neurotransmitter substance P, acetylcholine esterase, leucine-enkephalin, and c-Fos protein expression. However, there are few reports addressing changes in neurotransmitter expression following manual acupuncture and electroacupuncture against visceral traction pain.OBJECTIVE： To explore changes in neurotransmitter expression in the ileum and protein expression in the medullary visceral zone of visceral traction pain rats undergoing pretreatment of emulational manual acupuncture, and to investigate the differences between emulational manual acupuncture and electroacupuncture.DESIGN, TIME AND SETTING： The randomized, controlled study was performed at the Biomedical Engineering Laboratory, Shanghai University of Traditional Chinese Medicine, Shanghai, China from August 2008 to July 2009.MATERIALS： G6805 electroacupuncture apparatus （Shanghai Medical Electronic Machine Factory, China） and ZSF-I acupuncture manipulation simulation therapeutic system （Chinese Medical Engineering Room, Shanghai University of Traditional Chinese Medicine, Shanghai China） were used in the present study.METHODS： A total of 40 male Sprague Dawley rats were equally and randomly assigned to sham surgery, model, emulational manual acupuncture and electroacupuncture groups. In the emulational manual acupuncture and electroacupuncture groups, emulational manual acupuncture and electroacupuncture were applied at bilateral Zusanli （ST 36） acupoints for 30 minutes, and models of visceral traction pain were established immediately.MAIN OUTCOME MEASURES： Substance P expression, c-Fos and glial fibrillary acidic protein expression were measured using immunohistochemistry. Acetylcholine esterase activity was examined utilizing a colorimetric method. Leucine-enkephalin content was detected using a radioimmune assay. Degree of pain in rats was assessed by pain score.RESULTS： Pain score, substance P expression in the ileum, acetylcholine esterase activity, expression of c-Fos protein and glial fibrillary acidic protein in the medullary visceral zone were significantly decreased following pretreatment of emulational manual acupuncture and electroacupuncture in rats with visceral traction pain （P〈0.05）. Compared with the electroacupuncture group, the leucine-enkephalin content was significantly increased, and pain score was significantly diminished in the emulational manual acupuncture group （P〈0.05）.CONCLUSION： Emulational manual acupuncture pretreatment decreases acetylcholine esterase activity, increases leucine-enkephalin release, downregulates expression of c-Fos protein and glial fibrillary acidic protein and ultimately inhibits visceral traction pain by reducing substance P release. The effectiveness in inhibiting visceral traction pain is greater when using emulational manual acupuncture compared with electroacupuncture. This is because emulational manual acupuncture effectively increases leucine-enkephalin release.

Electrophysiology as a tool to unravel the origin of pancreatic pain

Intense abdominal pain is the most common symptom in chronic pancreatitis, but the underlying mechanisms are not completely understood and pain management remains a significant clinical challenge.The focus of pain origin in chronic pancreatitis traditionally has been on the pancreatic gland, assuming pain to originate in the pancreas or its surrounding organs. However, research in the last decade points to abnormal central nervous system pain processing.For this reason, electroencephalography has been receiving increasing attention. In contrast to imaging methods such as functional magnetic resonance and positron emission tomography, electroencephalogram has excellent temporal resolution making it possible to investigate central processing of pain on a millisecond time scale. Moreover, continuously advancing methodology made it possible to explore brain sources responsible for generation of evoked potentialsand hence to study brain reorganization due to pain in chronic pancreatitis. The aim of this review is to give an overview of the current methods and findings in electroencephalography as a tool to unravel the origin of pancreatic pain.

Extracellular signal-regulated kinase, substance P and neurokinin-1 are involved in the analgesic mechanism of herb-partitioned moxibustion

Herb-partitioned moxibustion can effectively mitigate visceral pain, a major symptom in inflammatory bowel disease, but the analgesic lnechanism is still unclear. Moreover, extracellular signal-regulated kinase, substance P, and neurokinin-1 are involved in formation of central hyperalgesia. Thus, we postulated that the analgesic effect of herb-partitioned moxibustion may be associated with these factors. Accordingly, in this study, we established an inflammatory bowel disease visceral pain model in rat by enema with a mixed solution of 5% trinitrobenzenesulfonic acid and 50% ethanol. Bilateral Tianshu （ST25） and Qihai （CV6） points were selected for herb-partitioned moxi- bustion. Our results showed that herb-partitioned moxibustion improved visceral pain and down-regulated extracellular signal-regulated kinase, substance P, and neurokinin-1 protein and mRNA expression in dorsal root ganglia. These results indicate that down-regulation of extracellular signal-regulated kinase, substance E and neurokinin-1 protein and mRNA may be a central mechanism for the analgesic effect of herb-partitioned moxibustion.

Mechanism of acupuncture regulating visceral sensation and mobility

Chinese ancient medical scientists have long focused on the internal and external contacts between acupoints on the surface of the body and the viscera.The Miraculous Pivot(it is one of the earliest medical classics in China)stated,“Twelve regular channels belong to the zang-fu organs internally,and connect to the extremities and joints externally.”Traditional Chinese medicine considers acupoints as defined areas where the Qi of viscera and meridians are transfused.These include the reaction points of visceral diseases on the body surface as well as the acupuncture trigger points that promote the flow of Qi and blood,and regulate visceral function.Chinese ancient medical scientists classified the specificity of the main acupoints in the body based on the meridian doctrine,which has been instructing clinical application for about 2000 years.Laws on the domino effect of acupoints have mainly focused on conclusions to clinical experiences.Indications of some acupoints exceed the practical paradigm since the excessive extension occurred during theory derivation.The current research direction on acupuncture focuses on three aspects:the effectiveness of acupuncture and moxibustion;the relevances and associations between meridians and viscera;and the physical and chemical properties and relevant physical basis of acupoints.The relevance between meridians and viscera is the central theory in the meridian doctrine,and acupoints are regarded as an important link in the relationship between meridians and viscera.Specific relationships between acupoints and target organs exist.Stimulating different acupoints on the body surface can help deal with different diseases,especially visceral diseases.In addition,acupoints have a dual function of reflecting and treating visceral diseases.There is no systemic research available on acupoint specificity,despite current knowledge and clinical experiences,which results in a weak foundation for acupuncture theory.This study focuses on the relevance and associations between meridians and viscera.A summary of the mechanisms of acupuncture regulating visceral sensation and mobility and the specific relationships between acupoints and their target organs are presented in this review.