BACKGROUND: Acupuncture and moxibustion against visceral noxious stimulation present different mechanisms in the peripheral and central nervous systems, involving release of neurotransmitter substance P, acetylcholin...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.展开更多
BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diar...BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea(IBS-D)was investigated in the present study.AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D.METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls.The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores.The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint.Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1(TRPV1)expression were examined following 5-HT2B receptor antagonist adminis-tration.Changes in visceral sensitivity after administration of the TRPV1 antago-INTRODUCTION Irritable bowel syndrome(IBS)is a chronic functional bowel disorder characterized by recurrent abdominal pain with altered bowel habits that affects approximately 15%of the population worldwide[1].IBS significantly impacts the quality of life of patients.Although the pathogenesis of IBS is not completely understood,the role of abnormal visceral sensitivity in IBS has recently emerged[2,3].5-Hydroxytryptamine(5-HT)is known to play a key role in the physiological states of the gastrointestinal tract.Plasma 5-HT levels in IBS with diarrhea(IBS-D)patients were greater than those in healthy controls[4],suggesting a possible role of 5-HT in the pathogenesis of IBS-D.The serotonin receptor 2(5-HT2 receptor)family comprises three subtypes:5-HT2A,5-HT2B,and 5-HT2c.All 5-HT2 receptors exhibit 46%-50%overall sequence identity,and all of these receptors preferentially bind to Gq/11 to increase inositol phosphates and intracellular calcium mobilization[5].5-HT2B receptors are widely expressed throughout the gut,and experimental evidence suggests that the primary function of 5-HT2B receptors is to mediate contractile responses to 5-HT through its action on smooth muscle[6].The 5-HT2B receptor is localized to both neurons of the myenteric nerve plexus and smooth muscle in the human colon.The 5-HT2B receptor mediates 5-HT-evoked contraction of longitudinal smooth muscle[6].These findings suggest that the 5-HT2B receptor could play an important role in modulating colonic motility,which could affect sensory signaling in the gut.Other laboratories have shown that the 5-HT2B receptor participates in the development of mechanical and formalin-induced hyperalgesia[7,8].A 5-HT2B receptor antagonist reduced 2,4,6-trinitrobenzene sulfonic acid(TNBS)and stress-induced visceral hyperalgesia in rats[9,10].However,the role of the 5-HT2B receptor in IBS-D patients and in acetic acid-and wrap restraint-induced IBS-D rat models was not investigated.展开更多
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 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.展开更多
BACKGROUND Visceral hypersensitivity and psychological performance are the main pathophysiological mechanisms of irritable bowel syndrome(IBS).Previous studies have found that cholecystokinin(CCK)can enhance colon mov...BACKGROUND Visceral hypersensitivity and psychological performance are the main pathophysiological mechanisms of irritable bowel syndrome(IBS).Previous studies have found that cholecystokinin(CCK)can enhance colon movement and that serotonin transporter(SERT)is a transmembrane transport protein with high affinity for 5-hydroxytryptamine,which can rapidly reuptake 5-hydroxytryptamine and then regulate its action time and intensity.We speculate that SERT and CCK might play a role in the pathogenesis of diarrheapredominant IBS(IBS-D)by affecting visceral sensitivity and the brain-gut axis.AIM To determine SERT and CCK levels in IBS-D patients diagnosed using Rome IV criteria and to analyze their associations with abdominal pain,visceral hypersensitivity and psychological performance.METHODS This study collected data from 40 patients with IBS-D at the China-Japan Friendship Hospital from September 2017 to April 2018 and 18 healthy controls.The severity of abdominal pain,visceral sensitivity and psychological performance were evaluated in IBS-D patients and healthy controls,the levels of SERT and CCK in plasma and colonic mucosa were evaluated,and the correlations between them were analyzed.RESULTS There were significant differences in the initial sensation threshold(31.00±8.41 mL vs 52.22±8.09 mL,P<0.001),defecating sensation threshold(51.75±13.57 mL vs 89.44±8.73 mL,P<0.001)and maximum tolerable threshold(97.25±23.64 mL vs 171.11±20.83 mL,P<0.001)between the two groups.IBS-D patients had more severe anxiety(7.78±2.62 vs 2.89±1.02,P<0.001)and depressive(6.38±2.43 vs 2.06±0.73,P<0.001)symptoms than healthy controls.Significant differences were also found in mucosal CCK(2.29±0.30 vs 1.66±0.17,P<0.001)and SERT(1.90±0.51 vs 3.03±0.23,P<0.001)between the two groups.There was a significant positive correlation between pain scores and mucosal CCK(r=0.96,0.93,0.94,P<0.001).Significant negative correlations between anxiety(r=-0.98;P<0.001),depression(r=-0.99;P<0.001),pain evaluation(r=-0.96,-0.93,-0.95,P<0.001)and mucosal SERT were observed.CONCLUSION IBS-D patients had psychosomatic disorders and visceral hypersensitivity.SERT and CCK might be involved in the pathogenesis of IBS-D by regulating the braingut axis and affecting visceral sensitivity.This provides a new potential method for identifying a more specific and effective therapeutic target.展开更多
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 i...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.展开更多
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 es...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.展开更多
AIM: To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome (IBS). Dysfunction ...AIM: To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome (IBS). Dysfunction of modulatory mechanisms would be expected to also result in changes of somatic sensory function. METHODS: Endogenous pain modulatory mechanisms were assessed using heterotopic stimulation and somatic and visceral sensory testing in IBS. Pain intensities (visua analogue scale, VAS 0-100) during suprathreshold recta distension with a barostat, cold pressor stimulation of the foot and during both stimuli simultaneously (heterotopic stimulation) were recorded in 40 female patients with IBS and 20 female healthy controls. RESULTS: Rectal hypersensitivity (defined by 95% CI of controls) was seen in 21 (53%), somatic hypersensitivity in 22 (55%) and both rectal and somatic hypersensitivity in 14 of these IBS patients. Heterotopic stimulation decreased rectal pain intensity by 6 (-11 to -1) in controls, but increased rectal pain by 2 (-3 to +6) in all IBS patients (P < 0.05) and by 8 (-2 to +19) in IBS patients with somatic and visceral hypersensitivity (P < 0.02). CONCLUSION: A majority of IBS patients had abnormal endogenous pain modulation and somatic hypersensitivity as evidence of central sensitization.展开更多
Deep visceral pain is frequent and presents major challenges in pain management, since its pathophysiology is still poorly understood. One way to optimize treatment of visceral pain is to improve knowledge of the mech...Deep visceral pain is frequent and presents major challenges in pain management, since its pathophysiology is still poorly understood. One way to optimize treatment of visceral pain is to improve knowledge of the mechanisms behind the pain and the mode of action of analgesic substances. This can be achieved through stand-ardized experimental human pain models. Experimental pain models in healthy volunteers are advantageous for evaluation of analgesic action, as this is often diff icult to assess in the clinic because of confounding factors such as sedation, nausea and general malaise. These pain models facilitate minimizing the gap between knowledge gained in animal and human clinical studies. Combining experimental pain studies and pharmacokinetic stud- ies can improve understanding of the pharmacokinetic-pharmacodynamic relationship of analgesics and, thus, provide valuable insight into optimal clinical treatment of visceral pain. To improve treatment of visceral pain, it is important to study the underlying mechanisms of pain and the action of analgesics used for its treatment. An experimental pain model activates different modalities and can be used to investigate the mechanism of action of different analgesics in detail. In combination with pharmacokinetic studies and objective assessment such as electroencephalography, new information re-garding a given drug substance and its effects can be obtained. Results from experimental human visceral pain research can bridge the gap in knowledge between animal studies and clinical condition in patients suffering from visceral pain, and thus constitute the missing link in translational pain research.展开更多
AIM To investigate the effects of herb-partitioned moxibustion(HPM) on phosphorylation of mitogen-activated extracellular signal-regulated kinase(MEK)1, extracellular signal-regulated kinase(ERK)1/2 and c AMP response...AIM To investigate the effects of herb-partitioned moxibustion(HPM) on phosphorylation of mitogen-activated extracellular signal-regulated kinase(MEK)1, extracellular signal-regulated kinase(ERK)1/2 and c AMP response element binding protein(CREB) in spinal cord of rats with chronic inflammatory visceral pain(CIVP), and to explore the central mechanism of HPM in treating CIVP.METHODS Male Sprague-Dawley rats were randomized into normal, model, HPM, sham-HPM, MEK-inhibitor and dimethyl sulfoxide(DMSO) groups. The CIVP model was established using an enema mixture of trinitrobenzene sulfonic acid and ethanol. HPM was applied at bilateral Tianshu(ST25) and Qihai(CV6) acupoints in the HPM group, while in the sham-HPM group, moxa cones and herb cakes were only placed on the same points but not ignited. The MEK-inhibitor and DMSO groups received L5-L6 intrathecal injection of U0126 and 30% DMSO, respectively. Abdominal withdrawal reflex(AWR), mechanical withdrawal threshold(MWT) and thermal withdrawal latency(TWL) were applied for the assessment of pain behavior. The colonic tissue was observed under an optical microscope after hematoxylin-eosin staining. Expression of phosphor(p)MEK1, p ERK1/2 and p CREB in rat spinal cord was detected using Western blotting. The levels of MEK, ERK and CREB m RNA in rat spinal cord were detected using real-time polymerase chain reaction. RESULTS Compared with the normal group, the AWR scores were increased significantly(P < 0.01) and the MWT and TWL scores were decreased significantly(P < 0.05) in the model, sham-HPM and DMSO groups. Compared with the model group, the AWR scores were decreased significantly(P < 0.01) and the MWT and TWL scores were increased significantly in the HPM and MEK-inhibitor groups(P < 0.05). Compared with the sham-HPM and DMSO groups, the AWR scores were decreased significantly(P < 0.01) and the MWT and TWL scores were increased significantly(P < 0.05) in the HPM and MEK-inhibitor groups. Compared with the normal group, the expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were increased significantly in the model, sham-HPM and DMSO groups(P < 0.01 or < 0.05). Compared with the model group, the expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were reduced significantly in the HPM and MEK-inhibitor groups(P < 0.01 or < 0.05). Compared with the sham-HPM and DMSO groups, expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were reduced significantly in the HPM and MEK-inhibitor groups(P < 0.01 or < 0.05). CONCLUSION HPM down-regulates protein phosphorylation of MEK1, ERK1/2 and CREB, and m RNA expression of MEK, ERK and CREB, inhibiting activation of the MEK/ERK/CREB signaling pathway in the spinal cord of CIVP rats, which is possibly a critical central mechanism of the analgesic effect of HPM.展开更多
Voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability,and their abnormal activity is related to several pathological processes,including cardiac arrhythmias,epilepsy,neurod...Voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability,and their abnormal activity is related to several pathological processes,including cardiac arrhythmias,epilepsy,neurodegenerative diseases,spasticity and chronic pain.In particular,chronic visceral pain,the central symptom of functional gastrointestinal disorders such as irritable bowel syndrome,is a serious clinical problem that affects a high percentage of the world population.In spite of intense research efforts and after the dedicated decade of pain control and research,there are not many options to treat chronic pain conditions.However,there is a wealth of evidence emerging to give hope that a more refined approach may be achievable.By using electronic databases,available data on structural and functional properties of VGSCs in chronic pain,particularly functional gastrointestinal hypersensitivity,were reviewed.We summarize the involvement and molecular bases of action of VGSCs in the pathophysiology of several organic and functionalgastrointestinal disorders.We also describe the efficacy of VGSC blockers in the treatment of these neurological diseases,and outline future developments that may extend the therapeutic use of compounds that target VGSCs.Overall,clinical and experimental data indicate that isoform-specific blockers of these channels or targeting of their modulators may provide effective and novel approaches for visceral pain therapy.展开更多
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 expres...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展开更多
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 ...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.展开更多
基金the National Natural Science Foundation of China,No. 30572411
文摘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.
基金The Health Commission of Jinshan District,Shanghai,China,No.JSKJ-KTMS-2019-01The Youth Research Foundation of Jinshan Hospital of Fudan University,No.JYQN-JC-202101 and No.JYQN-JC-202216The Reserve Discipline Construction of Jinshan Hospital of Fudan University,No.HBXK-2021-2.
文摘BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea(IBS-D)was investigated in the present study.AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D.METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls.The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores.The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint.Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1(TRPV1)expression were examined following 5-HT2B receptor antagonist adminis-tration.Changes in visceral sensitivity after administration of the TRPV1 antago-INTRODUCTION Irritable bowel syndrome(IBS)is a chronic functional bowel disorder characterized by recurrent abdominal pain with altered bowel habits that affects approximately 15%of the population worldwide[1].IBS significantly impacts the quality of life of patients.Although the pathogenesis of IBS is not completely understood,the role of abnormal visceral sensitivity in IBS has recently emerged[2,3].5-Hydroxytryptamine(5-HT)is known to play a key role in the physiological states of the gastrointestinal tract.Plasma 5-HT levels in IBS with diarrhea(IBS-D)patients were greater than those in healthy controls[4],suggesting a possible role of 5-HT in the pathogenesis of IBS-D.The serotonin receptor 2(5-HT2 receptor)family comprises three subtypes:5-HT2A,5-HT2B,and 5-HT2c.All 5-HT2 receptors exhibit 46%-50%overall sequence identity,and all of these receptors preferentially bind to Gq/11 to increase inositol phosphates and intracellular calcium mobilization[5].5-HT2B receptors are widely expressed throughout the gut,and experimental evidence suggests that the primary function of 5-HT2B receptors is to mediate contractile responses to 5-HT through its action on smooth muscle[6].The 5-HT2B receptor is localized to both neurons of the myenteric nerve plexus and smooth muscle in the human colon.The 5-HT2B receptor mediates 5-HT-evoked contraction of longitudinal smooth muscle[6].These findings suggest that the 5-HT2B receptor could play an important role in modulating colonic motility,which could affect sensory signaling in the gut.Other laboratories have shown that the 5-HT2B receptor participates in the development of mechanical and formalin-induced hyperalgesia[7,8].A 5-HT2B receptor antagonist reduced 2,4,6-trinitrobenzene sulfonic acid(TNBS)and stress-induced visceral hyperalgesia in rats[9,10].However,the role of the 5-HT2B receptor in IBS-D patients and in acetic acid-and wrap restraint-induced IBS-D rat models was not investigated.
基金supported by the Key Technologies R&D program of Henan Province,China(No.201503178)
文摘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.
基金Supported by the National Key Technology Support Program during “12th Five-Year Plan”period of China,No.2014BAI08B00the Leapforward Development Program for Beijing Biopharmaceutical Industry(G20),No. Z171100001717008.
文摘BACKGROUND Visceral hypersensitivity and psychological performance are the main pathophysiological mechanisms of irritable bowel syndrome(IBS).Previous studies have found that cholecystokinin(CCK)can enhance colon movement and that serotonin transporter(SERT)is a transmembrane transport protein with high affinity for 5-hydroxytryptamine,which can rapidly reuptake 5-hydroxytryptamine and then regulate its action time and intensity.We speculate that SERT and CCK might play a role in the pathogenesis of diarrheapredominant IBS(IBS-D)by affecting visceral sensitivity and the brain-gut axis.AIM To determine SERT and CCK levels in IBS-D patients diagnosed using Rome IV criteria and to analyze their associations with abdominal pain,visceral hypersensitivity and psychological performance.METHODS This study collected data from 40 patients with IBS-D at the China-Japan Friendship Hospital from September 2017 to April 2018 and 18 healthy controls.The severity of abdominal pain,visceral sensitivity and psychological performance were evaluated in IBS-D patients and healthy controls,the levels of SERT and CCK in plasma and colonic mucosa were evaluated,and the correlations between them were analyzed.RESULTS There were significant differences in the initial sensation threshold(31.00±8.41 mL vs 52.22±8.09 mL,P<0.001),defecating sensation threshold(51.75±13.57 mL vs 89.44±8.73 mL,P<0.001)and maximum tolerable threshold(97.25±23.64 mL vs 171.11±20.83 mL,P<0.001)between the two groups.IBS-D patients had more severe anxiety(7.78±2.62 vs 2.89±1.02,P<0.001)and depressive(6.38±2.43 vs 2.06±0.73,P<0.001)symptoms than healthy controls.Significant differences were also found in mucosal CCK(2.29±0.30 vs 1.66±0.17,P<0.001)and SERT(1.90±0.51 vs 3.03±0.23,P<0.001)between the two groups.There was a significant positive correlation between pain scores and mucosal CCK(r=0.96,0.93,0.94,P<0.001).Significant negative correlations between anxiety(r=-0.98;P<0.001),depression(r=-0.99;P<0.001),pain evaluation(r=-0.96,-0.93,-0.95,P<0.001)and mucosal SERT were observed.CONCLUSION IBS-D patients had psychosomatic disorders and visceral hypersensitivity.SERT and CCK might be involved in the pathogenesis of IBS-D by regulating the braingut axis and affecting visceral sensitivity.This provides a new potential method for identifying a more specific and effective therapeutic target.
文摘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.
基金NIDDK,No.5R01DK111819-03 and No.5R01DK032346-28National Natural Science Foundation of China,No.81571326.
文摘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.
基金Supported by Natural Science Foundation of Jiangsu Province,NO.BK2005033Medical Foundation of Department of Health,Jiangsu Province, No. H200325+1 种基金Natural Science Foundation of Department of Education, Jiangsu Province, No. 04kJB320127Medical Foundation of Department of Health, Zhejiang Province, No. 2004A084
文摘瞄准:证实内脏的疼痛经由颜色为表面的扩张(CRD ) 建模并且由在老鼠测量腹的屈肌反射(AWR ) 的分数评估 CRD 的行为的回答的效率。方法:称 180-240 g 的 38 只男 SD 老鼠被用来建立内脏的疼痛模型。老鼠与 7 厘米 intra-anally 被插入在醚麻醉下面的长灵活的乳胶汽球,和由与空气使汽球膨胀的表面的扩张在从麻醉恢复以后被成为 30 min 的颜色。五个 AWR 分数(到 AWR4 的 AWR0 ) 被用来估计有害内脏的刺激的紧张。它被认为是最低压(kPa ) 的阀值。因为腹的 flatting 被颜色导致表面的扩张。结果:到下降冒号和直肠的扩张的精力旺盛的 AWR 在 100% 被发现醒着测试的老鼠。越高扩张的压力,越 higher AWR 的分数。0, 2.00, 3.33, 5.33 和 8.00 kPa 的扩张压力生产了不同 AWR 分数(P【0.05 ) 。AWR 的痛觉阈为在起始的终结(第一 1-3 扩张) 以后的多达 80 min 是不变的,吝啬的阀值是 3.69+/-0.35 kPa。吗啡硫酸盐的全身的管理在一个剂量依赖者和 naloxone 提高了内脏的疼痛的阀值可逆举止。结论:在表面的扩张能估计的颜色期间获得 AWR 有害内脏的刺激的紧张。到内脏的痛觉阈清楚、不变、可靠的 CRD 的腹部(AWR 3 ) 的 Flatting。这个疼痛模型和它的行为的评价对关于内脏的疼痛和止痛剂的研究好。
基金the Brain-Gut Research Group, Berne, Switzerland
文摘AIM: To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome (IBS). Dysfunction of modulatory mechanisms would be expected to also result in changes of somatic sensory function. METHODS: Endogenous pain modulatory mechanisms were assessed using heterotopic stimulation and somatic and visceral sensory testing in IBS. Pain intensities (visua analogue scale, VAS 0-100) during suprathreshold recta distension with a barostat, cold pressor stimulation of the foot and during both stimuli simultaneously (heterotopic stimulation) were recorded in 40 female patients with IBS and 20 female healthy controls. RESULTS: Rectal hypersensitivity (defined by 95% CI of controls) was seen in 21 (53%), somatic hypersensitivity in 22 (55%) and both rectal and somatic hypersensitivity in 14 of these IBS patients. Heterotopic stimulation decreased rectal pain intensity by 6 (-11 to -1) in controls, but increased rectal pain by 2 (-3 to +6) in all IBS patients (P < 0.05) and by 8 (-2 to +19) in IBS patients with somatic and visceral hypersensitivity (P < 0.02). CONCLUSION: A majority of IBS patients had abnormal endogenous pain modulation and somatic hypersensitivity as evidence of central sensitization.
文摘Deep visceral pain is frequent and presents major challenges in pain management, since its pathophysiology is still poorly understood. One way to optimize treatment of visceral pain is to improve knowledge of the mechanisms behind the pain and the mode of action of analgesic substances. This can be achieved through stand-ardized experimental human pain models. Experimental pain models in healthy volunteers are advantageous for evaluation of analgesic action, as this is often diff icult to assess in the clinic because of confounding factors such as sedation, nausea and general malaise. These pain models facilitate minimizing the gap between knowledge gained in animal and human clinical studies. Combining experimental pain studies and pharmacokinetic stud- ies can improve understanding of the pharmacokinetic-pharmacodynamic relationship of analgesics and, thus, provide valuable insight into optimal clinical treatment of visceral pain. To improve treatment of visceral pain, it is important to study the underlying mechanisms of pain and the action of analgesics used for its treatment. An experimental pain model activates different modalities and can be used to investigate the mechanism of action of different analgesics in detail. In combination with pharmacokinetic studies and objective assessment such as electroencephalography, new information re-garding a given drug substance and its effects can be obtained. Results from experimental human visceral pain research can bridge the gap in knowledge between animal studies and clinical condition in patients suffering from visceral pain, and thus constitute the missing link in translational pain research.
基金Supported by National Natural Science Foundation of China,No.81273843 and No.81674073National Key Basic Research Program of China(973 Program)+1 种基金No.2015CB554501Project of Shanghai Municipal Commission of Health and Family Planning,No.20144Y0153 and No.2017BR047
文摘AIM To investigate the effects of herb-partitioned moxibustion(HPM) on phosphorylation of mitogen-activated extracellular signal-regulated kinase(MEK)1, extracellular signal-regulated kinase(ERK)1/2 and c AMP response element binding protein(CREB) in spinal cord of rats with chronic inflammatory visceral pain(CIVP), and to explore the central mechanism of HPM in treating CIVP.METHODS Male Sprague-Dawley rats were randomized into normal, model, HPM, sham-HPM, MEK-inhibitor and dimethyl sulfoxide(DMSO) groups. The CIVP model was established using an enema mixture of trinitrobenzene sulfonic acid and ethanol. HPM was applied at bilateral Tianshu(ST25) and Qihai(CV6) acupoints in the HPM group, while in the sham-HPM group, moxa cones and herb cakes were only placed on the same points but not ignited. The MEK-inhibitor and DMSO groups received L5-L6 intrathecal injection of U0126 and 30% DMSO, respectively. Abdominal withdrawal reflex(AWR), mechanical withdrawal threshold(MWT) and thermal withdrawal latency(TWL) were applied for the assessment of pain behavior. The colonic tissue was observed under an optical microscope after hematoxylin-eosin staining. Expression of phosphor(p)MEK1, p ERK1/2 and p CREB in rat spinal cord was detected using Western blotting. The levels of MEK, ERK and CREB m RNA in rat spinal cord were detected using real-time polymerase chain reaction. RESULTS Compared with the normal group, the AWR scores were increased significantly(P < 0.01) and the MWT and TWL scores were decreased significantly(P < 0.05) in the model, sham-HPM and DMSO groups. Compared with the model group, the AWR scores were decreased significantly(P < 0.01) and the MWT and TWL scores were increased significantly in the HPM and MEK-inhibitor groups(P < 0.05). Compared with the sham-HPM and DMSO groups, the AWR scores were decreased significantly(P < 0.01) and the MWT and TWL scores were increased significantly(P < 0.05) in the HPM and MEK-inhibitor groups. Compared with the normal group, the expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were increased significantly in the model, sham-HPM and DMSO groups(P < 0.01 or < 0.05). Compared with the model group, the expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were reduced significantly in the HPM and MEK-inhibitor groups(P < 0.01 or < 0.05). Compared with the sham-HPM and DMSO groups, expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were reduced significantly in the HPM and MEK-inhibitor groups(P < 0.01 or < 0.05). CONCLUSION HPM down-regulates protein phosphorylation of MEK1, ERK1/2 and CREB, and m RNA expression of MEK, ERK and CREB, inhibiting activation of the MEK/ERK/CREB signaling pathway in the spinal cord of CIVP rats, which is possibly a critical central mechanism of the analgesic effect of HPM.
文摘Voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability,and their abnormal activity is related to several pathological processes,including cardiac arrhythmias,epilepsy,neurodegenerative diseases,spasticity and chronic pain.In particular,chronic visceral pain,the central symptom of functional gastrointestinal disorders such as irritable bowel syndrome,is a serious clinical problem that affects a high percentage of the world population.In spite of intense research efforts and after the dedicated decade of pain control and research,there are not many options to treat chronic pain conditions.However,there is a wealth of evidence emerging to give hope that a more refined approach may be achievable.By using electronic databases,available data on structural and functional properties of VGSCs in chronic pain,particularly functional gastrointestinal hypersensitivity,were reviewed.We summarize the involvement and molecular bases of action of VGSCs in the pathophysiology of several organic and functionalgastrointestinal disorders.We also describe the efficacy of VGSC blockers in the treatment of these neurological diseases,and outline future developments that may extend the therapeutic use of compounds that target VGSCs.Overall,clinical and experimental data indicate that isoform-specific blockers of these channels or targeting of their modulators may provide effective and novel approaches for visceral pain therapy.
文摘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
文摘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.