Pregabalin inhibits accelerated defecation and decreased colonic nociceptive threshold in sensitized rats

Pregabalin, a ligand of α₂δ subunits of voltage-gated calcium channels, reduces visceral hypersensitivity associated with irritable bowel syndrome. However, effects of pregabalin on bowel function are not well described. We investigated the effects of pregabalin on bowel dysfunction and colonic nociceptive threshold in sensitized rats. Increased fecal pellet output was evoked by non-ulcerogenic stress. Decreased colonic nociceptive threshold was induced in separate rats by administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the lumen of the proximal colon. Fecal pellet output was significantly increased during 2 h restraint stress. Oral pregabalin (10-100 mg/kg, p.o.) inhibited this increased fecal output dose-dependently, but did not change fecal output in naïve rats. The response threshold to distension of the non-inflamed distal colon was significantly decreased seven days after TNBS administration. An anti-hyperalgesic effect of pregabalin (30-100 mg/kg, p.o.) that opposed the decreased colonic nociceptive threshold in TNBS-sensitized rats was observed, but nociceptive thresholds were not changed in naïve rats. Moreover, pregabalin was more potent in reducing disturbed defecation compared with reduction in nociceptive threshold to distension in TNBS-sensitized rats. This is the first report that pregabalin modulates stress-induced defecation in rats. These data indicate that pregabalin can ameliorate both altered defecation and decreases in colonic nociceptive threshold, suggesting that pregabalin might warrant investigation for the treatment of irritable bowel syndrome.     

Role of TRPV1 and TRPA1 in visceral hypersensitivity to colorectal distension during experimental colitis in rats

The aim of the present study is to investigate the effects of TRPV1 and TRPA1 receptor antagonists and their synergism on the visceromotor responses during experimental colitis in rats. Colitis was induced in rats by a TNBS/ethanol enema at day 0 and was assessed at day 3 using endoscopy, histology and a myeloperoxidase assay. The visceromotor response to colorectal distension (10–80 mmHg) was evaluated in conscious rats before (control condition) and 3 days after 2,4,6-trinitrobenzene sulfonic acid (TNBS) administration (colitis condition). At day 3, visceromotor responses were assessed before and after treatment with a TRPV1 (BCTC) or TRPA1 (TCS-5861528) receptor antagonist either alone or in combination and either after intraperitoneal or intrathecal administration. Endoscopy, microscopy and myeloperoxidase activity indicated severe colonic tissue damage 3 days after TNBS administration. Colorectal distension-evoked visceromotor responses demonstrated a 2.9-fold increase during acute colitis (day 3) compared to control conditions. Intraperitoneal and intrathecal administration of BCTC or TCS-5861528 partially reversed the colitis-induced increase in visceromotor responses compared to control conditions (P<0.05). Intraperitoneal blockade of TRPA1 plus TRPV1 further decreased the enhanced visceromotor responses at high distension pressures (40–80 mmHg) compared to blockade of either TRPV1 or TRPA1 alone. This synergistic effect was not seen after combined intrathecal blockade of TRPA1 plus TRPV1. The present study demonstrates that in the rat, TRPV1 and TRPA1 play a pivotal role in visceral hypersensitivity at the peripheral and spinal cord level during acute TNBS colitis. Target interaction, however, is presumably mediated via a peripheral site of action.     

肠易激综合征大鼠内脏高敏感性与脑肠互动的研究

目的研究腹泻型肠易激综合征大鼠模型内脏敏感性的改变与c-fos在结肠及中枢神经系统异常表达的关系。方法采用乙酸灌肠法造成腹泻型肠易激综合征动物模型（A组,n=12）和对照组（B组,n=12）,造模后通过腹部回撤反应评分评价内脏敏感性;用印度墨汁肠道染色法观察小肠蠕动,以墨汁在小肠中移行的距离占整段小肠长度的百分比来观察小肠推进蠕动的变化;应用免疫组织化学染色及计算机图像分析系统半定量分析结肠及中枢神经系统c-fos表达。结果该模型符合腹泻型肠易激综合征特征,A组腹部回撤反应评分、结肠及中枢神经系统c-fos表达高于B组,两组差异有统计学意义（P〈0.05）。结论乙酸灌肠法造成腹泻型肠易激综合征大鼠模型内脏高敏感性,c-fos的高表达参与大鼠内脏高敏感的异常调节。     

NK1 receptor-mediated mechanisms regulate colonic hypersensitivity in the guinea pig

Neurokinin-1 (NK(1)) receptors activated by substance P (SP) are involved in the processing of nociceptive information and are a potential target for therapy of visceral pain. We have evaluated the role of NK(1) receptors using a selective antagonist of NK(1) receptors in two animal models of colorectal hypersensitivity. The behavioral response to colorectal distension was assessed in freely moving guinea pigs by recording visceromotor reflex contractions of the abdominal musculature. Colonic hypersensitivity was induced by intracolonic administration of a chemical irritant (0.6% of acetic acid), or by acute partial restraint stress. Sensitization was characterized by an exaggerated visceromotor response to a low level of colorectal distension (10 mm Hg). In both models of colonic hypersensitivity, oral administration of TAK-637 (0.1-10 mg/kg) normalized visceromotor responses. The intracerebroventricular (10 microg/kg) or intrathecal (10 microg/kg) administration of TAK-637 inhibited colonic hypersensitivity, suggesting an interaction with central NK(1) receptors. In contrast, TAK-637 had no effect on visceromotor responses to colorectal distension at 40 mm Hg in guinea pigs with normosensitive (nonsensitized) colons. In conclusion, central NK(1) receptors play a significant role in colonic hypersensitivity induced by visceral afferent nerve sensitization from gastrointestinal origin or acute psychosomatic stress, but not in the perception of colorectal distension in animals with normosensitive colons.     

Establishment and validation of a rabbit model for in vivo pharmacodynamic screening of tachykinin NK(2) antagonists

We attempted to establish and validate an in vivo pharmacodynamic (PD) rabbit model to screen tachykinin NK(2) receptor (NK(2)-R) antagonists using pharmacological and pharmacokinetic (PK)/PD analyses. Under urethane anesthesia, changes in intracolonic pressure associated with intravenous (i.v.) administration of a selective NK(2)-R agonist, βAla(8)-neurokinin A(4-10) (βA-NKA), was monitored as a PD marker. The analgesic effects of NK(2)-R antagonists were evaluated by monitoring visceromotor response (VMR) to colorectal distension in a rabbit model of visceral hypersensitivity induced by intracolonic treatment of acetic acid. Intravenous administration of βA-NKA induced transient colonic contractions dose-dependently, which were inhibited by the selective NK(2)-R antagonists in dose- and/or plasma concentration-dependent manners. The correlation between PD inhibition and plasma concentration normalized with the corresponding in vitro binding affinity was relatively high (r(2) = 0.61). Furthermore, the minimum effective doses on the VMR and ID(50) values calculated in the PD model were highly correlated (r(2) = 0.74). In conclusion, we newly established and validated a rabbit model of agonist-induced colonic contractions as a screening tool for NK(2)-R antagonists. In a drug discovery process, this PD model could enhance the therapeutic candidate selection for irritable bowel syndrome, pharmacologically connecting in vitro affinity for NK(2)-R with in vivo therapeutic efficacy.     

The antinociceptive effects of intravenous tianeptine in colorectal distension-induced visceral pain in rats: the role of 5-HT₃ receptors

Tianeptine is an unusual tricyclic antidepressant drug. In this study, we aimed to investigate the antinociceptive effect of tianeptine on visceral pain in rats and to determine whether possible antinociceptive effect of tianeptine is mediated by serotonergic (5-HT(2,3)) and noradrenergic (α(1,2)) receptor subtypes. Male Sprague Dawley rats (250-300 g) were supplied with a venous catheter, for drug administrations, and enameled nichrome electrodes, for electromyography, at external oblique musculature. Colorectal distension (CRD) was employed as the noxious visceral stimulus and the visceromotor response (VMR) to CRD was quantified electromyographically before and 5, 15, 30, 60, 90 and 120 min after tianeptine administration. Antagonists were administered 10 min before tianeptine for their ability to change tianeptine antinociception. Intravenous administration of tianeptine (2.5-20 mg/kg) produced a dose-dependent reduction in VMR. Administration of 5-HT(3) receptor antagonist ondansetron (0.5, 1 and 2 mg/kg), but not 5-HT(2) receptor antagonist ketanserine (0.5, 1 and 2 mg/kg), reduced the antinociceptive effect of tianeptine (10mg/kg). In addition, administration of α(1)-adrenoceptor antagonist prazosin (1 mg/kg) or α(2)-adrenoceptor antagonist yohimbine (1 mg/kg) did not cause any significant effect on the tianeptine-induced antinociception. Our data indicate that intravenous tianeptine exerts a pronounced antinociception against CRD-induced visceral pain in rats, and suggests that the antinociceptive effect of tianeptine appears to be mediated in part by 5-HT(3) receptors, but does not involve 5-HT(2) receptors or α-adrenoceptors.     

冬凌草片对炎症后肠易激综合征大鼠的治疗作用

目的 研究冬凌草片对炎症后肠易激综合征（Post-inflammatory Irritable Bowel Syndrome,PI-IBS）大鼠的治疗作用及其机制。方法 用2,4,6-三硝基苯磺酸制备PI-IBS大鼠模型,动物灌胃给予冬凌草片0.4,0.8,1.2 g·kg^-1·d^-1,连续2周。采用腹壁收缩实验测内脏痛阈值;水应激法评价结肠运动;免疫组化法考察嗜铬细胞数;液质联用法测血清素含量,并用免疫印迹法考察色氨酸羟化酶的表达。结果 与正常对照组相比,PI-IBS大鼠内脏痛阈值明显降低、结肠排便增多、肠嗜铬细胞增生、色氨酸羟化酶表达增多及血清素含量增高（P<0.05）。冬凌草片高剂量和中剂量给药可显著提高PI-IBS大鼠内脏痛阈值;显著减少结肠排便数量、肠嗜铬细胞数量、血清素含量和色氨酸羟化酶表达（P<0.05）。结论 冬凌草片通过减少肠道嗜铬细胞增生和血清素含量治疗PI-IBS大鼠内脏痛及结肠运动障碍。     

Effect of a 5HT3-antagonist (ondansetron) on rectal sensitivity and compliance in health and the irritable bowel syndrome

In some patients with the irritable bowel syndrome, rectal urgency and discomfort are major clinical problems and, under experimental conditions, these symptoms are perceived at lesser volumes of rectal distension than they are in asymptomatic controls. Further, a 5-hydroxytryptamine type-3 receptor antagonist increased the threshold for rectal discomfort in irritable bowel syndrome. Our aims were, (a) to measure rectal sensation during isobaric distensions of the rectum, and (b) to test the effect of another selective 5HT₃ antagonist, ondansetron 0.15 mg/kg, on rectal sensitivity, colonic tone, rectal tone and manometric responses. Ten healthy volunteers and five patients with diarrhoea-predominant irritable bowel syndrome were studied. A multilumen barostatmanometric assembly was placed in the descending colon, and a second barostat balloon was positioned in the rectum. Tone in the wall of the colon and rectum was measured by the barostat balloon volume during a constant pressure clamp, while intraluminal pressures were recorded by manometry; perceived sensations were also recorded before and after the intravenous administration of ondansetron or placebo in blinded fashion. Rectal resistance to stretch was greater and rectal urgency was induced by lower distending pressures in irritable bowel syndrome, however, basal tone in the rectum was similar in health and irritable bowel syndrome. Ondansetron did not change rectal sensitivity (first sensation or urgency) or tone. Rectal distension did not alter tone in the descending colon or colonic manometry; ondansetron did not influence any index of colonic function. We conclude that in diarrhoea-predominant irritable bowel syndrome there is reduced rectal compliance and the rectum is abnormally sensitive to a pressure stimulus, but this is not altered by 5HT₃-blockade with ondansetron at the dose used.     

The GABA(B) receptor agonist, baclofen, and the positive allosteric modulator, CGP7930, inhibit visceral pain-related responses to colorectal distension in rats

Activation of GABA(B) receptors by the selective agonist baclofen produces anti-nociceptive effects in animal models of somatic pain. The aim of the present study was to evaluate the effect of baclofen and the GABA(B) receptor positive allosteric modulator CGP7930 on pseudo-affective responses to colorectal distension in rats. Female Sprague-Dawley rats were subjected to repeated, noxious colorectal distension (CRD) (12 distensions at 80 mmHg, for 30 s with 5 min intervals). The visceromotor response (VMR) and cardiovascular responses (mean arterial blood pressure (ABP) and heart rate (HR)) to CRD were monitored in conscious, telemetrized animals. Baclofen (0.3-3 micromol/kg, i.v.) reduced the VMR to CRD dose-dependently, reaching a 61% maximal inhibition (p < 0.001). The highest doses of baclofen attenuated CRD-evoked increases in ABP by 17% (p > 0.05) and reduced the change in HR by 48% (p < 0.01). CGP7930 (3-30 micromol/kg, i.v.) reduced the VMR to CRD in a dose-dependent fashion with a maximal inhibition of 31% (p < 0.05). The highest dose of CGP7930 also attenuated the increase in ABP by 18% (p > 0.05) and inhibited the increase in HR by 24% (p < 0.05) associated with CRD. Neither baclofen nor CGP7930 affected colorectal compliance. The results suggest that activation of GABA(B) receptors produces anti-nociceptive effects in a rat model of mechanically induced visceral pain. While CGP7930 was less efficacious than baclofen overall, positive allosteric modulation of GABA(B) receptors may represent a valid approach in the treatment of visceral pain conditions, with the possibility of an improved safety profile compared to full agonism.     

Milnacipran is active in models of irritable bowel syndrome and abdominal visceral pain in rodents

The role of antidepressants in the treatment of visceral pain has not been extensively examined. Milnacipran, a serotonin/noradrenalin reuptake inhibitor, has recently been approved in the USA for fibromyalgia, a chronic pathology characterized by diffused/chronic musculoskeletal pain, and a high prevalence of irritable bowel syndrome. Here, we determined its antinociceptive efficacy in two visceral pain tests in rodents: the acetic acid-induced writhing model in mice and the butyrate/colonic distension assay in rats, a model of irritable bowel syndrome. Acute milnacipran (5-40 mg/kgi.p.) significantly and dose-dependently reduced writhing (72.2 ± 3.2 versus 17.0 ± 4.1 writhes at 40 mg/kg). Following repeated administration (40 m/kgi.p. for 5 days), milnacipran preserved its ability to significantly reduce writhing (76 ± 8.3 versus 21.1 ± 6.7 writhes). Similarly, in the butyrate model, acute milnacipran (17.5 and 35 mg/kg, i.p.) significantly and dose-dependently increased cramps induction thresholds (from 45.7 ± 5.7 to 66.3 ± 4.8 and 75.6 ± 2.9 mm Hg, for 17.5 and 35 mg/kg, respectively) and reduced the number of cramps (from 3.0 ± 0.8 to 1.2 ± 0.8 and 0.3 ± 0.3 following inflation of an intra-rectal balloon. To summarise, milnacipran was efficacious in the writhing test, after acute and semi-chronic administration. This effect was confirmed after acute administration in a more specific model of colonic hypersensitivity induced by butyrate. This suggests that milnacipran has potential clinical application in the treatment of visceral pain, such as in irritable bowel syndrome, highly co-morbid with fibromyalgia.     

大鼠溃疡性结肠炎模型的实验研究

目的对不同剂量的三硝基苯磺酸（ＴＮＢＳ）引起的大鼠溃疡性结肠炎（ＵＣ）模型进行观察和评价。方法采用一次性直肠注入大鼠ＴＮＢＳ（２５～１５０ｍｇ·ｋｇ－１）的３０％乙醇溶液，引起慢性炎症性肠疾病（ＩＢＤ），３ｗｋ后外死动物对各剂量下动物结肠的重量、髓过氧化物酶（ＭＰＯ）活性及组织形态学变化进行观察和评价。结果ＴＮＢＳ在１００～１５０ｍｇ·ｋｇ－１剂量下引起的ＵＣ肠壁明显增厚，炎症和溃疡至少维持７ｗｋ时间，ＭＰＯ活性值显著性升高，组织学检查发现粘膜及粘膜下层有大量中性粒细胞及淋巴细胞、巨噬细胞、纤维细胞浸润，肉芽组织及隐窝脓肿形成，５０ｍｇ·ｋｇ－１剂量时有一较轻度的损伤。２５ｍｇ·ｋｇ－１时对结肠的重量、ＭＰＯ活性及损伤指数都没有显著性改变（Ｐ＞０．０５）。结论用ＴＮＢＳ引起大鼠实验性ＵＣ，其溃疡和炎症维持一较长时间，这一病理特征为炎症性疾病防治药物的研究提供了条件；本模型的最佳剂量为１００ｍｇ·ｋｇ－１左右     

Effect of ginseng saponins on a rat visceral hypersensitivity model

The 5-hydroxytryptamine3A (5-HT3) receptor is closely related with irritable bowel syndrome (IBS) in enteric nervous systems. We previously demonstrated that ginseng total saponins (GTS, also called ginsenosides), the active ingredients of Panax ginseng, inhibit the activity of 5-HT3A receptor channels expressed in Xenopus laevis oocytes. Here, we further investigated whether the in vitro inhibitory effect of ginsenosides on 5-HT3A receptor channel activity is coupled to in vivo attenuation of IBS. A rat model of IBS was induced by colorectal distention (CRD) and intracolonic infusion of 0.6% acetic acid (CRD-acetic acid), and visceral hypersensitivity was assessed by counting the contractions in the external oblique muscles of conscious rats during the 10 min distention period. We found that oral administration of GTS significantly and dose-dependently inhibited CRD-acetic acid-induced visceral hypersensitivity. The EC50 was 5.5+/-4.7 mg/kg (95% confidence intervals: 1.2-15.7) and the inhibitory effect of GTS against visceral hypersensitivity persisted for 4 h. When we compared the effects of protopanaxadiol (PD) ginsenosides and protopanaxatriol (PT) ginsenosides against CRD-acetic acid-induced visceral hypersensitivity, we found that PT but not PD ginsenosides significantly attenuated the CRD-acetic acid-induced visceral hypersensitivity. These results indicate that PT ginsenosides of Panax ginseng might be the main active components for the attenuation of experimentally CRD-acetic acid-induced visceral hypersensitivity, and may be clinically relevant for the future treatment of IBS.     

雌激素对慢性内脏痛雌鼠的敏化作用及其机制

目的探讨雌激素对慢性内脏痛雌鼠痛反应的影响及其与脊髓NMDA受体的关系。方法在♀大鼠新生期给予数次结直肠扩张刺激,成年后分为高、低雌激素组,用腹外斜肌放电水平来评价成鼠内脏痛觉敏感性,用NMDA受体拮抗剂D(-)-2-amino-5-phosphonopentanoic acid(AP-5)鞘内给药比较两组大鼠脊髓NMDA受体的功能。结果 (1)模型鼠高雌激素组的内脏痛反应比低雌激素组的反应强。(2)AP-5鞘内给药对内脏痛反应的抑制作用在模型鼠两组中的差异无统计学意义。结论高雌激素可加重模型雌鼠的内脏痛反应,雌激素不能使模型雌鼠脊髓背角的NMDA受体功能上调。     

Responses of rat spinal neurons to distension of inflamed colon: role of tachykinin NK2 receptors

Tachykinin NK2 receptors are implicated in nociception and the control of intestinal motility. Here we examined their involvement in responses of spinal lumbosacral neurons with colon input to distension of normal or inflamed colon in anesthetized rats. The responses of single neurons to colorectal distension (5-80 mmHg), to electrical stimulation of the pelvic nerve (bypassing sensory receptors) and to somatic stimulation were characterized. The effect of cumulative doses of an NK2 receptor antagonist, MEN 11420 (10-1000 microg kg(-1) IV), on responses to these stimuli was tested in control conditions (n=6), or 45 min after intracolonic instillation of acetic acid (n=6). After colonic inflammation, neuronal responses to colorectal distension and pelvic nerve stimulation were significantly greater. MEN 11420 dose-dependently inhibited the enhanced responses to colorectal distension after inflammation (ID50=402+/-14 microg kg(-1)), but had no significant effect on responses to pelvic nerve stimulation or distension of the normal colon, suggesting a peripheral action selective for the inflamed colon. We conclude that MEN 11420 possesses peripheral anti-hyperalgesic effects on neuronal responses to colorectal distension. These results provide a neurophysiological basis for a possible use of tachykinin NK2 receptor antagonists in treating abdominal pain in irritable bowel syndrome patients.     

N-methyl-d-aspartate receptor antagonist therapy suppresses colon motility and inflammatory activation six days after the onset of experimental colitis in rats

We set out to investigate the time-dependent colon motility and inflammatory changes in a rodent model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in order to estimate the efficacy of N-methyl-d-aspartate (NMDA) receptor antagonist therapy administered 6 day after the acute inflammatory event. Anaesthetized Sprague-Dawley rats were randomized to control (n=6) or colitis groups (n=18). The endogenous NMDA receptor antagonist kynurenic acid (n=6) or the synthetic analog SZR-72 (n=6) was administered 6 day after TNBS induction. Large bowel motility parameters, macrohaemodynamics and serosal microcirculatory changes were recorded; the severity of colonic damage was monitored by using in vivo confocal laser endomicroscopy. Nitrite/nitrate and nitrotyrosine levels, and xanthine oxidoreductase and myeloperoxidase activities were determined on colon biopsies; plasma levels of TNF-α and IL-6 were compared with those under control and 1-day colitis (n=6) conditions. TNBS induction elevated the tissue inflammatory enzyme activities, proinflammatory cytokine release, and nitrite/nitrate and nitrotyrosine formation. The microscopic vascular and mucosal lesions were accompanied by significant increases in serosal microcirculation and frequent intestinal movements 6 day after colitis. The NMDA receptor antagonist treatments significantly decreased the signs of inflammatory activation and the levels of nitric oxide end-products, normalized the microcirculation and the rate of bowel movements in both NMDA receptor antagonist-treated colitis groups. Blockade of the enteric NMDA receptors 6 day after colitis induction concurrently influenced NO production-linked nitrosative stress and colon dysmotility and may therefore offer a possibility via which to inhibit the progression of inflammatory changes in the later phase of TNBS colitis.     

Protective effect of taurine on TNBS-induced inflammatory bowel disease in rats

We had previously reported that the protective effect of taurine against indomethacin-induced gastric mucosal injury was due to its antioxidant effects, which inhibited lipid peroxidation and neutrophil activation. In this study, we examined the effect of taurine on reducing the inflammatory parameters of trinitrobenzene sulfonic acid (TNBS)-induced inflammatory bowel disease (IBD), in rats. In order to induce IBD, ethanolic TNBS was given to rats intracolonically. Then they received 500 mg/kg/day of taurine orally and were sacrificed one week after IBD induction. While ulceration and inflammation of distal colon with formation of granuloma in the vehicle-treated IBD rats two days after administration of TNBS were observed, treatment with taurine ameliorated colonic damage and decreased the incidence of diarrhea and adhesion. Also, colon weight as an index of tissue edema, which was markedly increased in the IBD rats, became significantly lower after taurine treatment. Myeloperoxidase (MPO) activity in the vehicle-treated IBD rats was substantially increased, compared with that of normal control. The taurine-treated animals significantly reduced MPO activity (35% lower) when compared with that of the vehicle-treated animals. Taurine treatment decreased both basal and formyl-methionyl leucyl phenylalanine-stimulated reactive oxygen generation from colonic tissue in the IBD rats. These results suggest that the administration of taurine reduce the inflammatory parameters in this IBD rat model by increasing defending capacity against oxidative damage.     

Oral clonidine inhibits visceral pain-related viscerosomatic and cardiovascular responses to colorectal distension in rats

The alpha(2)-adrenoceptor agonist, clonidine, modulates colorectal sensorimotor functions in humans and, given intrathecally, has analgesic effects in the colorectal distension (CRD) model in rats. We tested the effects of systemic clonidine on the visceral pain-related viscerosomatic and autonomic cardiovascular responses to CRD and colonic compliance in rats using clinically relevant CRD protocols. The activity of the abdominal musculature (viscerosomatic response), monitored by electromyography and intracolonic manometry, and changes in arterial blood pressure and heart rate, monitored by telemetry, were assessed simultaneously in conscious rats during CRD. Pressure-volume relationships during CRD served as a measure of colonic compliance. Clonidine (50-200 nmol/kg, p.o.) dose-dependently inhibited the viscerosomatic response to phasic, noxious CRD (12 distension at 80 mm Hg). At 200 nmol/kg clonidine also attenuated the increase in blood pressure (70+/-7% inhibition, P<0.05) and heart rate (67+/-16% inhibition, P<0.05) associated to noxious CRD. Similar effects were observed after i.v. administration. Likewise, clonidine (200 nmol/kg, p.o.) reduced the response to ascending phasic CRD (10-80 mm Hg) and significantly increased the threshold pressure for pain-related responses. Clonidine (50 or 150 nmol/kg, i.p.) did not affect the pressure-volume relationship during phasic CRD (2-20 mm Hg). These results show that systemic clonidine, at doses devoid of visible side effects, has analgesic effects in the CRD model of visceral pain in rats without affecting colonic compliance. These observations confirm the analgesic activity of systemic clonidine on visceral pain, support the translational value of the rat CRD model to humans and show that manometry is more sensitive than electromyography detecting pain-related responses.     

Protective effects of glycyrrhizic acid by rectal treatment on a TNBS-induced rat colitis model

Objectives The research compared rectal and oral treatments with glycyrrhizic acid for trinitrobenzene sulfonic acid (TNBS)‐induced colitis in rats. Methods Wistar rats were randomly divided into seven groups: one normal and six with colitis, including TNBS, glycyrrhizic acid (2, 10 and 50 mg/kg, rectally treated and 10 mg/kg, orally treated) and sulfasalazine (positive control, 225 mg/kg rectally treated) groups. Colitis was induced by colonic administration of TNBS in 30% ethanol. Key findings There were significant pathological changes in colon in TNBS‐treated groups, and rectal glycyrrhizic acid significantly attenuated colitis. Myeloperoxidase, tumour necrosis factor‐α and interleukin‐1β of colon tissue or serum in the rectal glycyrrhizic acid groups were markedly reduced when compared with the TNBS group, and lower than in the orally treated glycyrrhizic acid group. It was further noted that, in vitro, glycyrrhizic acid (up to 100 µg/ml) inhibited interleukin‐6 and elevated interleukin‐10 production in lipopolysaccharide‐activated macrophages, and significantly inhibited proliferation of spleen lymphocytes, suggesting the immunoregulatory function of glycyrrhizic acid. Conclusions Rectally administered glycyrrhizic acid has significant protective effects against TNBS‐induced colitis in rats, and the rectal route may be a complementary treatment for inflammatory bowel disease.     

Effect of asimadoline, a kappa opioid agonist, on pain induced by colonic distension in patients with irritable bowel syndrome

BACKGROUND: Visceral hypersensitivity plays a major role in irritable bowel syndrome pathophysiology. Opioid kappa receptors on afferent nerves may modulate it and be the target for new irritable bowel syndrome treatments. AIM: This study evaluated the effect of the kappa opioid agonist asimadoline on perception of colonic distension and colonic compliance in irritable bowel syndrome patients. METHOD: Twenty irritable bowel syndrome female patients (Rome II criteria; 40 +/- 13 years) and hypersensitivity to colonic distension (Pain threshold < or = 32 mmHg) were included in a randomized double-blind cross-over trial comparing the effect of a single oral dose of asimadoline 0.5 mg or placebo on sensory thresholds (defined as a constant and sustained sensation) elicited by left colon phasic distension (5 mmHg steps, 5 min) up to a sensation of abdominal pain. Colonic compliance was compared by the slope of the pressure-volume curves. RESULTS: On asimadoline, pain threshold (mean +/- s.d.) (29.8 +/- 7.2 mmHg) was higher than on placebo (26.3 +/- 7.8 mmHg), difference not statistically significant (P = 0.1756, ANOVA). Area under curve of pain intensity rated at each distension step was significantly lower on asimadoline (89.3 +/- 33.9, ANOVA) than on placebo (108.1 +/- 29.7) (P = 0.0411). Thresholds of perception of nonpainful distensions were not altered on asimadoline, as compared with placebo. Colonic compliance was not different on placebo and asimadoline. CONCLUSION: Asimadoline decreases overall perception of pain over a wide range of pressure distension of the colon in irritable bowel syndrome patients, without altering its compliance. These data suggest that further studies should explore the potential benefit of asimadoline in treatment of pain in irritable bowel syndrome patients.     

The effect of leukotriene-B4 receptor antagonist, SC-41930, on acetic acid-induced colonic inflammation

SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-p ropyl- 2H-1-benzopyran-2-carboxylic acid, is a potent in vitro leukotriene-B4 (LTB4) receptor antagonist. LTB4 levels are elevated in colonic tissue of inflammatory bowel disease (IBD) patients which may account for the high degree of neutrophil (PMN) infiltration. The guinea pig acetic acid-induced colonic inflammation model has characteristics of IBD including PMN infiltration, edema, ulceration and necrosis. The model was used to evaluate the effect of SC-41930. SC-41930 was given orally, 30 min before and after intrarectal administration of 3% acetic acid. The PMN marker enzyme, myeloperoxidase, was measured along with histological evaluation to assess inflammation. Both parameters showed significantly less inflammation in SC-41930 treated animals with an oral ED50 of 20 mg/kg. These study results with an LTB4 receptor antagonist indicate a role for LTB4 in colonic inflammation and that an LTB4 receptor antagonist may be beneficial for treatment of IBD.