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Agents that modulate the activity of high-voltage gated calcium channels (HVCCs) exhibit experimentally and clinically significant effect by relieving visceral pain. Among these agents, the toxins Phα1β and ω-conotoxin MVIIA effectively reduce chronic pain in rodent models. The molecular mechanisms underlying the chronic pain associated with acute pancreatitis (AP) are poorly understood. Hypercalcemia is a risk factor; the role of cytosolic calcium is considered to be a modulator of pancreatitis. Blockade of Ca 2+ signals may be useful as a prophylactic treatment of pancreatitis. We explored the pathophysiological roles of three peptide toxins: Phα1β and its recombinant form CTK 01512-2-blockers of TRPA1 receptor and HVCCs and ω-conotoxin MVIIA, a specific blocker of N-type calcium channels in cerulein-induced AP. Cerulein injection elicits AP in rats, evidenced by an increase in hyperalgesic pain, inflammatory infiltration, amylase and lipase secretion, and reactive oxygen species, TNF-α, and p65 NF-κB levels. These effects of cerulein-induced AP were abolished by Phα1β and its recombinant form CTK 01512-2, whereas ω-conotoxin MVIIA had no effect on the induced increase in pancreatic enzyme secretion. Our results demonstrate that Phα1β and CTK 01512-2 toxins-antagonists of HVCCs and TRPA1 receptor presented an effective response profile, in the control of nociception and inflammatory process in the AP model in rats, without causing changes in spontaneous locomotion of the rats., (Copyright © 2020. Published by Elsevier B.V.)

TRPV1 are involved in the control of the gastrointestinal (GI) functions and pain sensation. Their activation induces pain but it is followed by desensitization, which in turn causes analgesia. The studies from the last two decades indicate that TRPV1 are involved in visceral hypersensitivity in the GI tract and pathogenesis of irritable bowel syndrome (IBS). Therefore, the aim of this study is to assess the action of fast desensitizing agonist of TRPV1, palvanil (N-palmitoyl-vanillamine), in the murine GI tract and on nociception to evaluate its potential application in the therapy of IBS. The effect of palvanil on smooth muscle contractility was evaluated using organ baths. The impact of palvanil on intestinal secretion was assessed in Ussing chambers. In vivo, the action of palvanil (0.1-1 mg/kg) was assessed in whole GI transit, fecal pellet output, and colonic bead expulsion tests. The antinociceptive potency of palvanil was tested in the mustard oil-induced pain test. Palvanil inhibited colonic contractions (evoked by electrical field stimulation, EFS) and decreased the ion transport in the colon stimulated with forskolin. It did not affect secretion in experiments with veratridine. In vivo, palvanil prolonged whole GI transit at all doses tested. At the lower dose tested, it accelerated colonic motility during first 60 min following injection. By contrast, at the dose of 1 mg/kg, colonic motility was inhibited. Palvanil induced antinociceptive action at all tested doses in mustard oil-induced pain test. TRPV1 fast-desensitizing compounds, i.e., palvanil, may be promising agents in the therapy of IBS since it modulates intestinal motility and reduces visceral pain.

The field of abdominal organ transplantation is multifaceted, with the clinician balancing recipient comorbidities, risks of the surgical procedure, and the pathophysiology of immunosuppression to ensure optimal outcomes. An underappreciated element throughout this process is acute pain management related to the surgical procedure. As the opioid epidemic continues to grow with increasing numbers of transplant candidates on opioids as well the increase in the development of enhanced recovery after surgery protocols, there is a need for greater focus on optimal postoperative pain control to minimize opioid use and improve outcomes. This review will summarize the physiology of acute pain in transplant recipients, assess the impact of opioid use on post-transplant outcomes, present evidence supporting nonopioid analgesia in transplant surgery, and briefly address the perioperative approach to the pretransplant recipient on opioids.

Background: Postcholecystectomy pain (PCP) is characterized by abdominal pain after cholecystectomy. However, prevention of PCP is not well known yet. The purpose of this study was to determine whether Rowachol might be useful in preventing PCP., Methods: Between May 2013 and January 2014, a total of 138 patients with gallbladder disease who were scheduled to undergo laparoscopic cholecystectomy were randomly assigned to orally receive 100 mg Rowachol or placebo three times daily for 3 months after surgery. Abdominal pain was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire., Results: Incidence of PCP in the placebo group (n = 9, 14.3%) was higher than that in the Rowachol group (n = 3, 4.7%) with statistically marginal significance (P = 0.08). Risk factor analysis implicated PCP with increased difficulty in performing LC, more frequent pathology with acute cholecystitis, and absence of postoperative Rowachol treatment. Multivariate analysis revealed that greater difficulty of laparoscopic cholecystectomy (HR = 5.78, 95% CI 1.36-24.40, P < 0.05), and absence of postoperative Rowachol treatment (HR = 2.54, 95% CI 1.10-10.39, P < 0.05) were independent risk factors for development of PCP., Conclusion: Rowachol might be beneficial for prevention of PCP after laparoscopic cholecystectomy., (Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial., Methods: By using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects. The sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n = 28) or placebo (n = 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis. The primary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension., Results: TRPV1 responses of submucosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their pre-incubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidazole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P = .024), and reduced abdominal pain scores (ebastine 39 ± 23 vs placebo 62 ± 22; P = .0004)., Conclusions: In studies of rectal biopsy specimens from patients, we found that HRH1-mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS. ClinicalTrials.gov no: NCT01144832., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aim: To systematically evaluate the effect of intraperitoneal local anesthetic on pain characteristics after laparoscopic cholecystectomy (LC)., Methods: We searched MEDLINE, EMBASE, and the Cochrane Library. Randomized controlled trials in English that compared the effect of intraperitoneal administration of local anesthetics on pain with that of placebo or nothing after elective LC under general anesthesia were included. The primary outcome variables analyzed were the combined scores of abdominal, visceral, parietal, and shoulder pain after LC at multiple time points. We also extracted pain scores at resting and dynamic states., Results: We included 39 studies of 3045 patients in total. The administration of intraperitoneal local anesthetic reduced pain intensity in a resting state after laparoscopic cholecystectomy: abdominal [standardized mean difference (SMD) = -0.741; 95%CI: -1.001 to -0.48, P < 0.001]; visceral (SMD = -0.249; 95%CI: -0.493 to -0.006, P = 0.774); and shoulder (SMD = -0.273; 95%CI: -0.464 to -0.082, P = 0.097). Application of intraperitoneal local anesthetic significantly reduced the incidence of shoulder pain (RR = 0.437; 95%CI: 0.299 to 0.639, P < 0.001). There was no favorable effect on resting parietal or dynamic abdominal pain., Conclusion: Intraperitoneal local anesthetic as an analgesic adjuvant in patients undergoing laparoscopic cholecystectomy exhibited beneficial effects on postoperative abdominal, visceral, and shoulder pain in a resting state.

Background: Endoscopic submucosal dissection (ESD) has been revealed as an effective treatment of early gastric neoplasm and should be performed under sedation with adequate pain control. Magnesium sulfate has analgesic, sedative, and sympatholytic properties. This study examined the effects of intravenous magnesium 50 mg/kg administered before ESD for gastric neoplasm on analgesic and sedative consumptions during ESD and pain after ESD., Methods: In this randomized, double-blind, and prospective study, patients undergoing ESD randomly received either intravenous magnesium sulfate 50 mg/kg (magnesium group n = 30) or the same volume of normal saline (control group n = 30) over 10 min before the start of sedation. Fentanyl consumption during ESD was the primary end point. Hemodynamics was recorded during the procedure, and abdominal pain was evaluated at 30 min, 6 h, and 24 h after ESD., Results: During ESD, fentanyl consumption was 24% less in the magnesium group than in the control group (96 ± 27 vs. 126 ± 41 μg, mean ± SD; p = 0.002), although there was no significant difference in propofol consumption (p = 0.317). In addition, magnesium attenuated the elevation of mean blood pressure at the time of epinephrine submucosal injection (p = 0.038) and 5 min after submucosal dissection (p = 0.004). Less patients of the magnesium group compared to the control group requested for additional analgesics in the recovery room (14 vs. 38 %, p = 0.043), and the intensity of abdominal pain was lower at 30 min after ESD in the magnesium group (p = 0.034)., Conclusions: A single-dose intravenous administration of magnesium 50 mg/kg before sedation reduced analgesic requirements both during and after ESD for gastric neoplasm without adverse effects. In addition, magnesium contributed to stable hemodynamics throughout the procedure.

Antihyperglycemic and antinociceptive activity studies were carried out with methanolic extract of whole plants of Bacopa monnieri, respectively, through oral glucose tolerance test and gastric pain model induced by acetic acid in Swiss albino mice. In OGTT (oral glucose tolerance tests) conducted with glucose-challenged mice, the extract, administered at four doses of 50, 100, 200 and 400mg per kg body weight, dose-dependently and significantly inhibited the increase in serum glucose concentrations, respectively, by 33.3, 34.2, 42.1 and 44.2%. A standard antihyperglycemic drug, glibenclamide, when administered at a dose of 10mg per kg body weight, inhibited increase in serum glucose concentration by 50.7%. From the results, it can be concluded that the methanolic extract of the plant possess significant antihyperglycemic potential. In antinociceptive activity tests, administration of the extract at the aforementioned four doses also significantly and dose-dependently reduced the number of acetic acid-induced gastric constrictions in mice. The percent inhibitions in gastric constrictions were, respectively, 43.4, 46.6, 50.0, and 53.4 at the above four doses. A reference antinociceptive drug, aspirin, when administered at a dose of 200 mg per kg body weight, reduced the number of gastric constrictions by 40.0%. Thus the extract at even the lowest dose of 50 mg, demonstrated antinociceptive activity better than that of aspirin, and which activity was much more than aspirin at the other three higher doses tested. The results demonstrate that the plant can be an excellent candidate for further studies towards isolation of antihyperglycemic and pain-killing compounds.

Objectives: Oxidative stress is strongly implicated in the pathogenesis of chronic pancreatitis (CP); however, clinical studies evaluating antioxidant therapy (AOT) in the management of CP pain have yielded conflicting results. The aim of this meta-analysis was to evaluate the efficacy of AOT in pain reduction in CP patients., Methods: Two authors independently conducted a comprehensive literature search from inception to December 2013. Relative risk (RR) and 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel and DerSimonian-Laird methods., Results: Eight studies involving 446 patients (234 in AOT and 212 in control group) were included. Overall, CP patients who received AOT had significant reduction in pain compared with the control group (RR, 0.73; 95% CI, 0.58-0.91; P = 0.006). In the subgroup analysis, studies with predominantly alcoholic CP patients (RR, 0.60; 95% CI, 0.47-0.77; P < 0.0001) and studies with mean age of patients 42 years or older (RR, 0.66; 95% CI, 0.49-0.89; P = 0.006) showed significant benefit of AOT over placebo., Conclusions: This is the first meta-analysis to summarize all the available evidence and show benefit of AOT in pain reduction in CP patients. There is a pressing need for well-designed larger studies with longer follow-up to better define the patient and disease factors favoring response, the optimal formulation, and duration of AOT.

Background: Salvinorin A (SA) is a potent anti-inflammatory diterpene isolated from the Mexican plant S. divinorum. Recently we showed that the novel SA analog, PR-38 has an inhibitory effect on mouse gastrointestinal (GI) motility mediated by opioid and cannabinoid (CB) receptors. The aim of the study was to characterize possible anti-inflammatory and antinociceptive action of PR-38 in the mouse GI tract., Methods: Macro- and microscopic colonic damage scores and myeloperoxidase activity were determined after intraperitoneal (i.p.), intracolonic (i.c.), and per os (p.o.) administration of PR-38 in the trinitrobenzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS) models of colitis in mice. Additionally, MOP, KOP and CB1 protein expression was determined using Western blot analysis of mouse colon samples. The antinociceptive effect of PR-38 was examined based on the number of behavioral responses to i.c. instillation of mustard oil (MO)., Results: The i.p. (10 mg/kg, twice daily), i.c. (10 mg/kg, twice daily) and p.o. (20 mg/kg, once daily) administration of PR-38 significantly attenuated TNBS- and DSS-induced colitis in mice. The effect of PR-38 was partially blocked by the KOP antagonist nor-binaltorphimine and CB1 antagonist AM 251. Western blot analysis showed a significant increase of MOP, KOP and CB1 receptor expression during colonic inflammation, which was reversed to the control levels by the administration of PR-38. PR-38 significantly decreased the number of pain responses after i.c. instillation of MO in the TNBS-treated mice., Conclusions: Our results suggest that PR-38 has the potential to become a valuable anti-inflammatory and analgesic therapeutic for the treatment of GI inflammation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: To characterize the antinociceptive action of the novel melatonin receptor (MT) agonists, Neu-P11 and Neu-P12 in animal models of visceral pain., Methods: Visceral pain was induced by intracolonic (ic) application of mustard oil or capsaicin solution or by intraperitoneal (ip) administration of acetic acid. Neu-P11, Neu-P12, or melatonin were given ip or orally and their effects on pain-induced behavioral responses were evaluated. To identify the receptors involved, the non-selective MT1/MT2 receptor antagonist luzindole, the MT2 receptor antagonist 4-P-PDOT, or the μ-opioid receptor antagonist naloxone were injected ip or intracerebroventricularly (icv) prior to the induction of pain., Results: Orally and ip administered melatonin, Neu-P11, and Neu-P12 reduced pain responses in a dose-dependent manner. Neu-P12 was more effective and displayed longer duration of action compared to melatonin. The antinociceptive effects of Neu-P11 or Neu-P12 were antagonized by ip or icv. administered naloxone. Intracerebroventricularly, but not ip administration of luzindole or 4-P-PDOT blocked the antinociceptive actions of Neu-P11 or Neu-P12., Conclusion: Neu-P12 produced the most potent and long-lasting antinociceptive effect. Further development of Neu-P12 for future treatment of abdominal pain seems promising.

Ethnopharmacological Relevance: Scorzonera species are mainly used against inflammation and to relieve pain in Turkish traditional medicine. Therefore, we aimed to assess in vivo anti-inflammatory and antinociceptive activities of the aerial part and root extracts of Scorzonera acuminata, Scorzonera cana var. alpina, Scorzonera cana var. jacquiniana, Scorzonera cana var. radicosa, Scorzonera cinerea, Scorzonera eriophora, Scorzonera incisa, Scorzonera laciniata ssp. laciniata, Scorzonera parviflora and Scorzonera sublanata., Materials and Methods: For the anti-inflammatory activity evaluation carrageenan, PGE(2) and serotonin-induced hind paw edema and 12-O-tetradecanoyl-13-acetate (TPA)-induced mouse ear edema models were used. p-Benzoquinone-induced abdominal constriction test was employed in mice for the assessment of antinociceptive activity. Furthermore chemical composition of the tested extracts was investigated qualitatively and quantitatively by using RP-HPLC method. Some phenolic acids and flavonoids were used as standards., Results: Extracts prepared from the aerial parts of Scorzonera cana var. jacquiniana, Scorzonera cinerea, Scorzonera eriophora, Scorzonera incisa and Scorzonera parviflora showed significant inhibitory effect on carrageenan and PGE(2)-induced hind paw edema model as well as on p-benzoquinone-induced abdominal constriction test. The extracts did not show any remarkable activity on serotonin-induced hind paw edema and TPA-induced mouse ear edema models. Chlorogenic acid was detected as major compounds in all the species investigated. Additionally, among the tested flavonoids, luteolin-7-glucoside, hyperoside and rutin were found to be in different amounts in Scorzonera species., Conclusion: The experimental data revealed that Scorzonera cana var. jacquiniana, Scorzonera cinerea, Scorzonera eriophora, Scorzonera incisa and Scorzonera parviflora possess significant anti-inflammatory and antinociceptive activity. It has been suggested that flavonoids and chlorogenic acid are partly responsible for mentioned activities of Scorzonera species., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The proposed curative properties of copper(II)-non-steroidal anti-inflammatory drugs (NSAIDs) have led to the development of numerous copper(II)-NSAID complexes with enhanced anti-inflammatory activity. In this work, the antinociceptive and toxic effects of two new coordination complexes: Cu₂(fen)₄(caf)₂ [fen: fenoprofenate anion; caf: caffeine] and Cu₂(fen)₄(dmf)₂ [dmf: N-N'-dimethylformamide] were evaluated in mice. The antinociceptive effect was evaluated with two models: acetic acid-induced writhing response and formalin test. For the sub-acute exposure, the complexes were added to the diet at different doses for 28days. Behavioral and functional nervous system parameters in a functional observational battery were assessed. Also, hematological, biochemical and histopathological studies were performed. Cu₂(fen)₄(caf)₂ and Cu₂(fen)₄(dmf)₂ significantly decreased the acetic acid-induced writhing response and the licking time on the late phase in the formalin test with respect to the control and fenoprofen salt groups. The sub-acute exposure to Cu₂(fen)₄(caf)₂ complex increased the motor activity, the number of rearings and the arousal with respect to the control and fenoprofen salt groups. These impaired parameters in mice exposed to Cu₂(fen)₄(caf)₂ can be attributable to the presence of caffeine as stimulating agent. On the other hand, all exposed groups decreased the urine pools in the functional observational battery and increased the plasmatic urea. These effects could be due to the decrease in the glomerular filtration caused by NSAIDs. In conclusion, both complexes Cu₂(fen)₄(dmf)₂ and Cu₂(fen)₄(caf)₂ were more potent antinociceptive agents than fenoprofen salt. Sub-acute exposure to different doses of these complexes did not produce significant changes in the parameters that evaluate toxicity., (© 2011 Elsevier B.V. All rights reserved.)

Unlabelled: We investigated the antinociceptive effects of AR-A014418, a selective inhibitor of glycogen synthase kinase-3β (GSK-3β) in mice. A 30-minute pretreatment with AR-A014418 (.1 and 1 mg/kg, intraperitoneal [ip]) inhibited nociception induced by an ip injection of acetic acid. AR-A014418 pretreatment (.1 and .3 mg/kg, ip) also decreased the late (inflammatory) phase of formalin-induced licking, without affecting responses of the first (neurogenic) phase. In a different set of experiments, AR-A014418 (.1-10 μg/site) coinjected intraplantarly (ipl) with formalin inhibited the late phase of formalin-induced nociception. Furthermore, AR-A014418 administration (1 and 10 ng/site, intrathecal [it]) inhibited both phases of formalin-induced licking. In addition, AR-A014418 coinjection (10 ng/site, it) inhibited nociception induced by glutamate, N-methyl-D-aspartate (NMDA), (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β) by 47 ± 12%, 48 ± 11%, 31 ± 8%, 46 ± 13%, and 44 ± 11%, respectively. In addition, a 30-minute pretreatment with NP031115 (3 and 10 mg/kg, ip), a different GSK-3 β inhibitor, also attenuated the late phase of formalin-induced nociception. Collectively, these results provide convincing evidence that AR-A014418, given by local, systemic, and central routes, produces antinociception in several mouse models of nociception. The AR-A014418-dependent antinociceptive effects were induced by modulation of the glutamatergic system through metabotropic and ionotropic (NMDA) receptors and the inhibition of the cytokine (TNF-α and IL-1β) signaling., Perspective: These results suggest that GSK-3β may be a novel pharmacological target for the treatment of pain., (Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) (PL) is a naturally occurring yellow pigment found in the plants of the Plumbaginaceae, Droseraceae, Ancistrocladaceae, and Dioncophyllaceae families. It has been reported that PL exhibits anticarcinogenic, anti-inflammatory, and analgesic activities. However, the mechanism underlying its anti-inflammatory action remains unknown. In the current study, we investigated and characterized the anti-inflammatory and analgesic effects of PL orally administrated in a range of dosages from 5 to 20 mg/kg. We also examined the role of nuclear factor κB (NF-κB) and proinflammatory cytokines and mediators in this effect. The results showed that PL significantly and dose-dependently suppressed the paw edema of rats induced by carrageenan and various proinflammatory mediators, including histamine, serotonin, bradykinin, and prostaglandin E(2). PL reduced the number of writhing episodes of mice induced by the intraperitoneal injection of acetic acid, but it did not reduce the writhing episode numbers induced by MgSO(4) in mice or prolong the tail-flick reaction time of rats to noxious thermal pain. Mechanistic studies showed that PL effectively decreased the production of the proinflammatory cytokines interleukin 1β, interleukin 6, and tumor necrosis factor α. It also inhibited the expression of the proinflammatory mediators inducible nitric-oxide synthase and cyclooxygenase 2, whereas it did not inhibit the expression of cyclooxygenase 1. Further studies demonstrated that PL suppressed inhibitor of κBα phosphorylation and degradation, thus inhibiting the phosphorylation of the p65 subunit of NF-κB. This study suggests that PL has a potential to be developed into an anti-inflammatory agent for treating inflammatory diseases.

The need for anesthesia or analgesia for performing hysteroscopy is still matter of debate. Many factors explain the lack of agreement about anesthesia in hysteroscopy depending on the instrumentation, technique employed, need of performing surgical procedure, operator skill and patients' characteristics. Diagnostic minihysteroscopy (3.5 mm or less in size) is less painful and easier to perform than hysteroscopy performed with instruments sized around 5 mm. Thanks to miniaturized instruments, office hysteroscopy allows a growing number of women to be treated in an office setting avoiding the operating room. The main limitation to its widespread use is pain and low patient tolerance. Intrauterine surgical procedures involving only the endometrial mucosa (biopsies, adhesiolisis, cervical and endometrial polyectomies) are not painful. For endometrial polypectomy size of polyps (<2.2m) and duration of the procedure (more than 15 min) are limiting factors. Most literature suggests that office hysteroscopy in experienced hands is a well-tolerated technique and requires the use of analgesics only in selected patients like women with previous caesarean section, history of chronic pelvic pain, anxiety and in menopause., (Copyright © 2010 AAGL. Published by Elsevier Inc. All rights reserved.)

Pregabalin, a ligand of alpha(2)delta 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 2h restraint stress. Oral pregabalin (10-100mg/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 (30-100mg/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., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Roots of Onosma species are used for the treatment of various disorders such as bronchitis, tonsillitis, hemorrhoids as well as alleviating pains in folk medicine in Turkey., Aim of the Study: The chloroform and ethanol (70%) extracts obtained from the roots of Onosma species (Boraginaceae) growing in Turkey, Onosma aucheranum DC., Onosma isauricum Boiss. and Heldr. (endemic), Onosma sericeum Willd., Onosma tauricum Pallas ex Willd. var. brevifolium DC. (endemic) and Onosma tauricum Pallas ex Willd. var. tauricum (Syn: Onosma velenovskyi Davidov) were evaluated for in vivo anti-inflammatory and antinociceptive activities., Materials and Methods: For the preliminary screening, carrageenan-induced hind paw edema for the anti-inflammatory activity and, p-benzoquinone-induced abdominal constriction test for the antinociceptive activity were used in mice., Results: The chloroform extracts from Onosma aucheranum and Onosma isauricum and ethanolic extracts from Onosma isauricum and Onosma sericeum demonstrated 28.0%, 34.3%, 24.6% and, 27.5% inhibition in p-benzoquinone-induced abdominal constriction test. The chloroform and ethanol (70%) extracts of Onosma isauricum and ethanol (70%) extract of Onosma sericeum also exhibited marked inhibition, ranging between 12.3-27.3%, 10.5-25.3%, 8.2-22.6%, respectively, in carrageenan-induced hind paw edema model at 100mg/kg dose without gastric damage and the activity was quite comparable to indomethacin (32.0-38.4% inhibition) as a reference sample. Neither death nor gastric bleeding was observed for any of the plant extracts during the acute toxicity evaluation., Conclusion: The experimental data demonstrated that Onosma aucheranum, Onosma isauricum and Onosma sericeum displayed remarkable anti-inflammatory and antinociceptive activities.

Background and Aims: Although numerous studies have evaluated outcomes pertaining to endoscopic retrograde cholangio-pancreatography (ERCP) complications, studies evaluating outcomes of management of post-ERCP pancreatitis are scant. This study evaluated the effectiveness of a standard treatment protocol in management of post-ERCP pancreatitis., Methods: This is a retrospective study of consecutive patients managed for post-ERCP pancreatitis, using a standard treatment protocol over a 3-year period. By protocol, patients received only intravenous fluids, narcotics, and analgesics for the first 24-72 h after admission. Oral intake was attempted when white cell count was normal or followed a downward trend, abdominal pain was absent or minimal without need for narcotics over a 12-h period, and serum lipase was less than three times normal range. For patients hospitalized beyond 72 h, an abdomen CT was obtained at days 4 and 10 to guide management. Intravenous antibiotics were administered only for patients with pancreatic necrosis. Jejunal feeding and a meperidine pump for pain control were initiated in symptomatic patients at day 4. Data on ERCP complications were collected prospectively and graded per consensus criteria. Effectiveness of the treatment protocol was evaluated by comparing clinical outcomes of patients managed by protocol versus those managed outside protocol., Results: 45 of 1976 patients (2.3%) who underwent ERCP developed post-ERCP pancreatitis. Of the 45 (female 31; mean age 43 years) patients, 32 were managed by protocol and 13 outside protocol. Protocol based management was associated with less severe disease as compared with those managed outside protocol (crude odds ratio (OR) = 11.2; 95% confidence interval (CI) = 1.9-68.7; P = 0.002). One patient managed outside protocol died of severe pancreatitis. When compared with those managed outside protocol, the median duration of hospital stay (7 vs 3 days; P = 0.01), the use of CT (100% vs 15.6%; P < 0.001), and the use of antibiotics (50% vs 3.1%; P = 0.01) were significantly lower in those managed by protocol. By multiple logistic regression, protocol-based management was associated with less severe disease (adjusted OR = 18.7; 95% CI = 2.6-132.1; P = 0.003) when adjusted for age, comorbidity, endotherapy and pancreatic stenting., Conclusions: A protocol-based management strategy was associated with less severe pancreatitis, shorter length of hospital stay, need for fewer imaging studies, and use of antibiotics. Prospective validation of these findings is justified.

The effect of a leukotriene D(4) receptor antagonist, (3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl(3-dimethyl amino-3-oxo propyl)thio)methyl)thio) propanoic acid (L-660,711; MK-571), was investigated on nociceptive responses in mice using three different assays: acetic-acid-induced abdominal constrictions, formalin response and tail-flick test. MK-571 (8-32 mg/kg, i.v.) produced dose-dependent protection against acetic-acid-induced abdominal constriction (ED(50)=30 mg/kg). The compound (10-80 mg/kg, i.p.) was also effective, in a dose-dependent manner, on the second phase of the formalin response (ED(50)=26 mg/kg). However, it had no effect on the first phase of the formalin response and in the tail-flick test. Naloxone (1 mg/kg, i.v.), an opioid antagonist, almost completely blocked the antinociceptive effect of MK-571 in both acetic-acid-induced abdominal constriction and the second phase of the formalin test. These results provide evidence for an antinociceptive action of MK-571 at peripheral sites and suggest that opioid mechanisms are involved.