Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 210
Filtrar
1.
United European Gastroenterol J ; 12(8): 1102-1113, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39106086

RESUMEN

BACKGROUND: Gelsectan® is a formulation of xyloglucan (XG), pea protein, grape seed extract (PPGS) and xylo-oligosaccharides (XOS). Our aim was to examine the effect of Gelsectan® on rectal sensitivity in an animal model, abdominal pain in irritable bowel syndrome with diarrhoea (IBS-D) subjects and intestinal permeability in both conditions. METHODS: Animals: Wistar rats received gavage with XOS, XG + PPGS or XG + PPGS + XOS, as a single dose or for 7 days before a partial restraint stress (PRS). Visceromotor response to rectal distension and total gut paracellular permeability to 51Cr-EDTA were assessed. Humans: IBS-D and control patients were involved. After initial colonoscopy with biopsy sampling Gelsectan® was administered to IBS-D patients for 12 weeks. Stool count and pain scores were documented. After treatment, colonoscopy was repeated. The permeability of biopsy samples was measured in Ussing-chambers. Adherent mucus layer, Muc-2 expression as well as TNFα, Interferon IFNγ were evaluated by histology/immunohistochemistry and ELISA assays, respectively. RESULTS: Animal studies: In control rats, PRS significantly increased visceromotor response as well as gut paracellular permeability. Single dose administration of XG + PPGS + XOS failed to reverse PRS, but 7 days of oral treatment reversed PRS-induced rectal hypersensitivity and gut hyperpermeability. Human studies: Gelsectan® treatment significantly reduced and abdominal pain. Intestinal permeability in IBS-D patients was elevated compared with controls, Gelsectan® restored permeability in the ascendent colon. Periodic acid-Schiff-stained mucus layer was significantly thinner in IBS-D patients compared with controls, In both segments, mucus thickness and the proportion of Muc-2 positive cells were not affected by Gelsectan® treatment. IFNγ tissue level in the sigmoid colon shows modest mucosal inflammation in IBS-D. CONCLUSIONS: Gelsectan® prevented rectal hypersensitivity in rats, abdominal pain in human and intestinal hyperpermeability in rat and human studies respectively. These effects involve restoration of gut permeability. Based on this translational study, Gelsectan® can be considered as an effective therapy for IBS-D symptoms.


Asunto(s)
Diarrea , Modelos Animales de Enfermedad , Glucanos , Mucosa Intestinal , Síndrome del Colon Irritable , Permeabilidad , Ratas Wistar , Xilanos , Animales , Síndrome del Colon Irritable/tratamiento farmacológico , Síndrome del Colon Irritable/complicaciones , Diarrea/tratamiento farmacológico , Diarrea/etiología , Humanos , Ratas , Masculino , Xilanos/farmacología , Xilanos/uso terapéutico , Xilanos/administración & dosificación , Femenino , Glucanos/farmacología , Glucanos/administración & dosificación , Glucanos/uso terapéutico , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Adulto , Dolor Visceral/tratamiento farmacológico , Dolor Visceral/etiología , Recto/patología , Persona de Mediana Edad , Oligosacáridos/administración & dosificación , Oligosacáridos/farmacología , Dolor Abdominal/etiología , Dolor Abdominal/tratamiento farmacológico
2.
Biomed Pharmacother ; 177: 116867, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38889634

RESUMEN

The aim of this study was to determine the anti-hypersensitivity activity of novel non-hallucinogenic compounds derived from iboga alkaloids (i.e., ibogalogs), including tabernanthalog (TBG), ibogainalog (IBG), and ibogaminalog (DM506), using mouse models of neuropathic (Chronic Constriction Injury; CCI) and visceral pain (dextrane sulfate sodium; DSS). Ibogalogs decreased mechanical hyperalgesia and allodynia induced by CCI in a dose- and timeframe-dependent manner, where IBG showed the longest anti-hyperalgesic activity at a comparatively lower dose, whereas DM506 displayed the quickest response. These compounds also decreased hypersensitivity induced by colitis, where DM506 showed the longest activity. To understand the mechanisms involved in these effects, two approaches were utilized: ibogalogs were challenged with the 5-HT2A receptor antagonist ketanserin and the pharmacological activity of these compounds was assessed at the respective 5-HT2A, 5-HT6, and 5-HT7 receptor subtypes. The behavioral results clearly demonstrated that ketanserin abolishes the pain-relieving activity of ibogalogs without inducing any effect per se, supporting the concept that 5-HT2A receptor activation, but not inhibition, is involved in this process. The functional results showed that ibogalogs potently activate the 5-HT2A and 5-HT6 receptor subtypes, whereas they behave as inverse agonists (except TBG) at the 5-HT7 receptor. Considering previous studies showing that 5-HT6 receptor inhibition, but not activation, and 5-HT7 receptor activation, but not inhibition, relieved chronic pain, we can discard these two receptor subtypes as participating in the pain-relieving activity of ibogalogs. The potential involvement of 5-HT2B/2 C receptor subtypes was also ruled out. In conclusion, the anti-hypersensitivity activity of ibogalogs in mice is mediated by a mechanism involving 5-HT2A receptor activation.


Asunto(s)
Alcaloides , Neuralgia , Receptor de Serotonina 5-HT2A , Dolor Visceral , Animales , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Masculino , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Ratones , Dolor Visceral/tratamiento farmacológico , Dolor Visceral/metabolismo , Alcaloides/farmacología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Modelos Animales de Enfermedad , Analgésicos/farmacología , Relación Dosis-Respuesta a Droga
3.
Drug Des Devel Ther ; 18: 1799-1810, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38828025

RESUMEN

Purpose: Oxycodone is a potent µ- and κ-opioid receptor agonist that can relieve both somatic and visceral pain. We assessed oxycodone- vs sufentanil-based multimodal analgesia on postoperative pain following major laparoscopic gastrointestinal surgery. Methods: In this randomised double-blind controlled trial, 40 adult patients were randomised (1:1, stratified by type of surgery) to receive oxycodone- or sufentanil-based multimodal analgesia, comprising bilateral transverse abdominis plane blocks, intraoperative dexmedetomidine infusion, flurbiprofen axetil, and oxycodone- or sufentanil-based patient-controlled analgesia. The co-primary outcomes were time-weighted average (TWA) of visceral pain (defined as intra-abdominal deep and dull pain) at rest and on coughing during 0-24 h postoperatively, assessed using the numerical rating scale (0-10) with a minimal clinically important difference of 1. Results: All patients completed the study (median age, 64 years; 65% male) and had adequate postoperative pain control. The mean (SD) 24-h TWA of visceral pain at rest was 1.40 (0.77) in the oxycodone group vs 2.00 (0.98) in the sufentanil group (mean difference=-0.60, 95% CI, -1.16 to -0.03; P=0.039). Patients in the oxycodone group had a significantly lower 24-h TWA of visceral pain on coughing (2.00 [0.83] vs 2.98 [1.26]; mean difference=-0.98, 95% CI, -1.66 to -0.30; P=0.006). In the subgroup analyses, the treatment effect of oxycodone vs sufentanil on the co-primary outcomes did not differ in terms of age (18-65 years or >65 years), sex (female or male), or type of surgery (colorectal or gastric). Secondary outcomes (24-h TWA of incisional and shoulder pain, postoperative analgesic usage, rescue analgesia, adverse events, and patient satisfaction) were comparable between groups. Conclusion: For patients undergoing major laparoscopic gastrointestinal surgery, oxycodone-based multimodal analgesia reduced postoperative visceral pain in a statistically significant but not clinically important manner. Trial Registration: Chinese Clinical Trial Registry (ChiCTR2100052085).


Asunto(s)
Analgésicos Opioides , Laparoscopía , Oxicodona , Dolor Postoperatorio , Dolor Visceral , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Analgesia Controlada por el Paciente , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/uso terapéutico , Dexmedetomidina/administración & dosificación , Dexmedetomidina/farmacología , Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Método Doble Ciego , Flurbiprofeno/análogos & derivados , Laparoscopía/efectos adversos , Oxicodona/administración & dosificación , Oxicodona/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Sufentanilo/administración & dosificación , Dolor Visceral/tratamiento farmacológico
4.
J Drug Target ; 32(8): 953-963, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38864378

RESUMEN

Nowadays, the pharmacological management of visceral hypersensitivity associated with colitis is ineffective. In this context, targeting purinergic P2X4 receptor (P2X4R), which can modulate visceral pain transmission, could represent a promising therapeutic strategy. Herein, we tested the pain-relieving effect of two novel and selective P2X4R antagonists (NC-2600 and NP-1815-PX) in a murine model of DNBS-induced colitis and investigated the mechanisms underlying their effect. Tested drugs and dexamethasone (DEX) were administered orally, two days after colitis induction. Treatment with tested drugs and DEX improved tissue inflammatory parameters (body weight, spleen weight, macroscopic damage, TNF and IL-1ß levels) in DNBS-rats. In addition, NC-2600 and NP-1815-PX attenuated visceral pain better than DEX and prevented the reduction of occludin expression. In in vitro studies, treatment of CaCo2 cells with supernatant from THP-1 cells, previously treated with LPS plus ATP, reduced the expression of tight junctions protein. By contrast, CaCo2 cells treated with supernatant from THP-1 cells, previously incubated with tested drugs, counteracted the reduction of tight junctions due to the inhibition of P2X4R/NLRP3/IL-1ß axis. In conclusion, these results suggest that the direct and selective inhibition of P2X4R represents a viable approach for the management of visceral pain associated with colitis via NLRP3/IL-1ß axis inhibition.


Asunto(s)
Colitis , Modelos Animales de Enfermedad , Antagonistas del Receptor Purinérgico P2X , Receptores Purinérgicos P2X4 , Dolor Visceral , Animales , Dolor Visceral/tratamiento farmacológico , Colitis/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/farmacología , Antagonistas del Receptor Purinérgico P2X/uso terapéutico , Receptores Purinérgicos P2X4/metabolismo , Ratas , Masculino , Humanos , Dexametasona/farmacología , Interleucina-1beta/metabolismo
5.
Drug Des Devel Ther ; 18: 2381-2392, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38911034

RESUMEN

Purpose: We aimed to evaluate the effect of intravenous esketamine combined with dexmedetomidine as supplemental analgesia in reducing intraoperative visceral pain during elective cesarean section under combined spinal-epidural anesthesia (CSEA). Patients and Methods: A total of 269 parturients scheduled for elective cesarean section under CSEA between May 2023 and August 2023 were assessed. The parturients were randomly allocated to receiving either intravenous infusion of 0.3-mg/kg esketamine combined with 0.5-µg/kg dexmedetomidine (group ED, n=76), 0.5-µg/kg dexmedetomidine (group D, n=76), or normal saline (group C, n=76) after umbilical cord clamping. The primary outcome was intraoperative visceral pain. Secondary outcomes included the visual analog scale (VAS) score for pain evaluation and other intraoperative complications. Results: The incidence of visceral pain was lower in group ED [9 (12.7%)] than in group D [32 (43.8%)] and group C [36 (48.6%), P <0.0001]. The VAS score was also lower in group ED when exploring abdominal cavity [0 (0), P <0.0001] and suturing the muscle layer [0 (0), P =0.036]. The mean arterial pressure was higher in group D [83 (9) mmHg] and group ED [81 (11) mmHg] than in group C [75 (10) mmHg, P <0.0001] after solution infusion. The heart rate after infusion of the solution was lower in group D [80 (12) bpm] than in group C [86 (14) bpm] and group ED [85 (12) bpm, P = 0.016]. The incidence of transient neurologic or mental symptoms was higher in group ED compared to group C and group D (76.1% vs 18.9% vs 23.3%, P<0.0001). Conclusion: During cesarean section, 0.3-mg/kg esketamine combined with 0.5-µg/kg dexmedetomidine can alleviate visceral traction pain and provide stable hemodynamics. Parturients receiving this regimen may experience transient neurologic or mental symptoms that can spontaneously resolve at the end of the surgery.


Some parturients endure experience indescribable pain and discomfort during fetal delivery. Esketamine combined with dexmedetomidine can alleviate this pain during cesarean section under combined spinal-epidural anesthesia. However, after intravenous injection of esketamine and dexmedetomidine, the parturients may experience nightmares, dizziness, hallucinations, and drowsiness, etc.


Asunto(s)
Anestesia Epidural , Anestesia Raquidea , Cesárea , Dexmedetomidina , Ketamina , Dolor Visceral , Humanos , Dexmedetomidina/administración & dosificación , Ketamina/administración & dosificación , Método Doble Ciego , Femenino , Adulto , Dolor Visceral/prevención & control , Dolor Visceral/tratamiento farmacológico , Embarazo , Quimioterapia Combinada , Procedimientos Quirúrgicos Electivos
6.
Phytother Res ; 38(8): 4177-4188, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38923108

RESUMEN

Inflammatory bowel disease (IBD) is a morbid condition characterized by relapsing-remitting inflammation of the colon, accompanied by persistent gut dysmotility and abdominal pain. Different reports demonstrated biological activities of aged black garlic (ABG), including anti-inflammatory and antioxidant effects. We aimed to investigate beneficial effects exerted by ABGE on colon inflammation by using ex vivo and in vivo experimental models. We investigated the anti-inflammatory effects of an ABG water extract (ABGE) on rat colon specimens exposed to E. coli lipopolysaccharide (LPS), a known ex vivo experimental model of ulcerative colitis. We determined gene expression of various biomarkers involved in inflammation, including interleukin (IL)-1ß, IL-6, nuclear factor-kB (NF-kB), tumor necrosis factor (TNF)-α. Moreover, we studied the acute effects of ABGE on visceral pain associated with colitis induced by 2,4-di-nitrobenzene sulfonic acid (DNBS) injection in rats. ABGE suppressed LPS-induced gene expression of IL-1ß, IL-6, NF-kB, and TNF-α. In addition, the acute administration of ABGE (0.03-1 g kg-1) dose-dependently relieved post-inflammatory visceral pain, with the higher dose (1 g kg-1) able to significantly reduce both the behavioral nociceptive response and the entity of abdominal contraction (assessed by electromyography) in response to colorectal distension after the acute administration in DNBS-treated rats. Present findings showed that ABGE could represent a potential strategy for treatment of colitis-associated inflammatory process and visceral pain. The beneficial effects induced by the extract could be related to the pattern of polyphenolic composition, with particular regard to gallic acid and catechin.


Asunto(s)
Antiinflamatorios , Colitis Ulcerosa , Modelos Animales de Enfermedad , Ajo , FN-kappa B , Extractos Vegetales , Dolor Visceral , Animales , Extractos Vegetales/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Ratas , Masculino , Antiinflamatorios/farmacología , Dolor Visceral/tratamiento farmacológico , Ajo/química , FN-kappa B/metabolismo , Lipopolisacáridos , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Interleucina-6/metabolismo , Hiperalgesia/tratamiento farmacológico , Colon/efectos de los fármacos , Ratas Sprague-Dawley , Ratas Wistar
7.
World J Gastroenterol ; 30(16): 2258-2271, 2024 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-38690023

RESUMEN

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most frequent and debilitating conditions leading to gastroenterological referrals. However, recommended treatments remain limited, yielding only limited therapeutic gains. Chitin-glucan (CG) is a novel dietary prebiotic classically used in humans at a dosage of 1.5-3.0 g/d and is considered a safe food ingredient by the European Food Safety Authority. To provide an alternative approach to managing patients with IBS, we performed preclinical molecular, cellular, and animal studies to evaluate the role of chitin-glucan in the main pathophysiological mechanisms involved in IBS. AIM: To evaluate the roles of CG in visceral analgesia, intestinal inflammation, barrier function, and to develop computational molecular models. METHODS: Visceral pain was recorded through colorectal distension (CRD) in a model of long-lasting colon hypersensitivity induced by an intra-rectal administration of TNBS [15 milligrams (mg)/kilogram (kg)] in 33 Sprague-Dawley rats. Intracolonic pressure was regularly assessed during the 9 wk-experiment (weeks 0, 3, 5, and 7) in animals receiving CG (n = 14) at a human equivalent dose (HED) of 1.5 g/d or 3.0 g/d and compared to negative control (tap water, n = 11) and positive control (phloroglucinol at 1.5 g/d HED, n = 8) groups. The anti-inflammatory effect of CG was evaluated using clinical and histological scores in 30 C57bl6 male mice with colitis induced by dextran sodium sulfate (DSS) administered in their drinking water during 14 d. HT-29 cells under basal conditions and after stimulation with lipopolysaccharide (LPS) were treated with CG to evaluate changes in pathways related to analgesia (µ-opioid receptor (MOR), cannabinoid receptor 2 (CB2), peroxisome proliferator-activated receptor alpha, inflammation [interleukin (IL)-10, IL-1b, and IL-8] and barrier function [mucin 2-5AC, claudin-2, zonula occludens (ZO)-1, ZO-2] using the real-time PCR method. Molecular modelling of CG, LPS, lipoteichoic acid (LTA), and phospholipomannan (PLM) was developed, and the ability of CG to chelate microbial pathogenic lipids was evaluated by docking and molecular dynamics simulations. Data were expressed as the mean ± SEM. RESULTS: Daily CG orally-administered to rats or mice was well tolerated without including diarrhea, visceral hypersensitivity, or inflammation, as evaluated at histological and molecular levels. In a model of CRD, CG at a dosage of 3 g/d HED significantly decreased visceral pain perception by 14% after 2 wk of administration (P < 0.01) and reduced inflammation intensity by 50%, resulting in complete regeneration of the colonic mucosa in mice with DSS-induced colitis. To better reproduce the characteristics of visceral pain in patients with IBS, we then measured the therapeutic impact of CG in rats with TNBS-induced inflammation to long-lasting visceral hypersensitivity. CG at a dosage of 1.5 g/d HED decreased visceral pain perception by 20% five weeks after colitis induction (P < 0.01). When the CG dosage was increased to 3.0 g/d HED, this analgesic effect surpassed that of the spasmolytic agent phloroglucinol, manifesting more rapidly within 3 wk and leading to a 50% inhibition of pain perception (P < 0.0001). The underlying molecular mechanisms contributing to these analgesic and anti-inflammatory effects of CG involved, at least in part, a significant induction of MOR, CB2 receptor, and IL-10, as well as a significant decrease in pro-inflammatory cytokines IL-1b and IL-8. CG also significantly upregulated barrier-related genes including muc5AC, claudin-2, and ZO-2. Molecular modelling of CG revealed a new property of the molecule as a chelator of microbial pathogenic lipids, sequestering gram-negative LPS and gram-positive LTA bacterial toxins, as well as PLM in fungi at the lowesr energy conformations. CONCLUSION: CG decreased visceral perception and intestinal inflammation through master gene regulation and direct binding of microbial products, suggesting that CG may constitute a new therapeutic strategy for patients with IBS or IBS-like symptoms.


Asunto(s)
Quitina , Colon , Modelos Animales de Enfermedad , Glucanos , Síndrome del Colon Irritable , Ratas Sprague-Dawley , Dolor Visceral , Animales , Síndrome del Colon Irritable/tratamiento farmacológico , Síndrome del Colon Irritable/fisiopatología , Masculino , Humanos , Colon/efectos de los fármacos , Colon/patología , Ratas , Dolor Visceral/tratamiento farmacológico , Dolor Visceral/fisiopatología , Dolor Visceral/metabolismo , Dolor Visceral/etiología , Quitina/farmacología , Glucanos/farmacología , Glucanos/administración & dosificación , Ratones , Prebióticos/administración & dosificación , Ácido Trinitrobencenosulfónico/toxicidad , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/fisiopatología , Colitis/patología , Células HT29
8.
Kaohsiung J Med Sci ; 40(6): 561-574, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38634140

RESUMEN

Slow transit constipation (STC) is one of the most common gastrointestinal disorders in children and adults worldwide. Paeoniflorin (PF), a monoterpene glycoside compound extracted from the dried root of Paeonia lactiflora, has been found to alleviate STC, but the mechanisms of its effect remain unclear. The present study aimed to investigate the effects and mechanisms of PF on intestinal fluid metabolism and visceral sensitization in rats with compound diphenoxylate-induced STC. Based on the evaluation of the laxative effect, the abdominal withdrawal reflex test, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry were used to detect the visceral sensitivity, fluid metabolism-related proteins, and acid-sensitive ion channel 3/extracellular signal-regulated kinase (ASIC3/ERK) pathway-related molecules. PF treatment not only attenuated compound diphenoxylate-induced constipation symptoms and colonic pathological damage in rats but also ameliorated colonic fluid metabolic disorders and visceral sensitization abnormalities, as manifested by increased colonic goblet cell counts and mucin2 protein expression, decreased aquaporin3 protein expression, improved abdominal withdrawal reflex scores, reduced visceral pain threshold, upregulated serum 5-hydroxytryptamine, and downregulated vasoactive intestinal peptide levels. Furthermore, PF activated the colonic ASIC3/ERK pathway in STC rats, and ASIC3 inhibition partially counteracted PF's modulatory effects on intestinal fluid and visceral sensation. In conclusion, PF alleviated impaired intestinal fluid metabolism and abnormal visceral sensitization in STC rats and thus relieved their symptoms through activation of the ASIC3/ERK pathway.


Asunto(s)
Canales Iónicos Sensibles al Ácido , Estreñimiento , Glucósidos , Sistema de Señalización de MAP Quinasas , Monoterpenos , Animales , Glucósidos/farmacología , Monoterpenos/farmacología , Monoterpenos/uso terapéutico , Canales Iónicos Sensibles al Ácido/metabolismo , Estreñimiento/tratamiento farmacológico , Estreñimiento/metabolismo , Ratas , Masculino , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratas Sprague-Dawley , Colon/metabolismo , Colon/efectos de los fármacos , Colon/patología , Tránsito Gastrointestinal/efectos de los fármacos , Acuaporina 3/metabolismo , Acuaporina 3/genética , Serotonina/metabolismo , Dolor Visceral/tratamiento farmacológico , Dolor Visceral/metabolismo
9.
Int Immunopharmacol ; 133: 112099, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38643709

RESUMEN

Visceral hypersensitivity resulting from compromised gut barrier with activated immune system is a key feature of irritable bowel syndrome (IBS). Corticotropin-releasing factor (CRF) and Toll-like receptor 4 (TLR4) activate proinflammatory cytokine signaling to induce these changes, which is one of the mechanisms of IBS. As activation of the NLRP3 inflammasome by lipopolysaccharide (LPS) or TLR4 leads to release interleukin (IL)-1ß, the NLRP3 inflammasome may be involved in the pathophysiology of IBS. Tranilast, an anti-allergic drug has been demonstrated to inhibit the NLRP3 inflammasome, and we evaluated the impact of tranilast on visceral hypersensitivity and colonic hyperpermeability induced by LPS or CRF (IBS rat model). Visceral pain threshold caused by colonic balloon distention was measured by monitoring abdominal muscle contractions electrophysiologically. Colonic permeability was determined by quantifying the absorbed Evans blue within the colonic tissue. Colonic protein levels of NLRP3 and IL-1ß were assessed by immunoblot or ELISA. Intragastric administration of tranilast (20-200 mg/kg) for 3 days inhibited LPS (1 mg/kg)-induced visceral hypersensitivity and colonic hyperpermeability in a dose-dependent manner. Simultaneously, tranilast also abolished these alterations induced by CRF (50 µg/kg). LPS increased colonic protein levels of NLRP3 and IL-1ß, and tranilast inhibited these changes. ß-hydroxy butyrate, an NLRP3 inhibitor, also abolished visceral hypersensitivity and colonic hyperpermeability caused by LPS. In contrast, IL-1ß induced similar GI alterations to LPS, which were not modified by tranilast. In conclusion, tranilast improved visceral pain and colonic barrier by suppression of the NLRP3 inflammasome in IBS rat models. Tranilast may be useful for IBS treating.


Asunto(s)
Colon , Inflamasomas , Síndrome del Colon Irritable , Proteína con Dominio Pirina 3 de la Familia NLR , ortoaminobenzoatos , Animales , Masculino , Ratas , Colon/efectos de los fármacos , Colon/metabolismo , Modelos Animales de Enfermedad , Hiperalgesia/tratamiento farmacológico , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Interleucina-1beta/metabolismo , Síndrome del Colon Irritable/tratamiento farmacológico , Síndrome del Colon Irritable/metabolismo , Lipopolisacáridos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , ortoaminobenzoatos/farmacología , ortoaminobenzoatos/uso terapéutico , Permeabilidad/efectos de los fármacos , Ratas Sprague-Dawley , Dolor Visceral/tratamiento farmacológico , Dolor Visceral/metabolismo
10.
Inflamm Bowel Dis ; 30(10): 1843-1851, 2024 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-38478397

RESUMEN

BACKGROUND: Transient receptor potential vanilloid 1 (TRPV1) cation channels, expressed on nociceptors, are well established as key contributors to abdominal pain in inflammatory bowel disease (IBD). Previous attempts at blocking these channels have been riddled with side effects. Here, we propose a novel treatment strategy, utilizing the large pore of TRPV1 channels as a drug delivery system to selectively inhibit visceral nociceptors. METHODS: We induced colitis in rats using intrarectal dinitrobenzene sulfonic acid. Visceral hypersensitivity, spontaneous pain, and responsiveness of the hind paws to noxious heat stimuli were examined before and after the intrarectal application of membrane-impermeable sodium channel blocker (QX-314) alone or together with TRPV1 channel activators or blockers. RESULTS: Intrarectal co-application of QX-314 with TRPV1 channel activator capsaicin significantly inhibited colitis-induced gut hypersensitivity. Furthermore, in the model of colitis, but not in naïve rats, QX-314 alone was sufficient to reverse gut hypersensitivity. The blockade of TRPV1 channels prevented this effect of QX-314. Finally, applying QX-314 alone to the inflamed gut inhibited colitis-induced ongoing pain. CONCLUSIONS: Selective silencing of gut nociceptors by a membrane-impermeable sodium channel blocker entering via exogenously or endogenously activated TRPV1 channels diminishes IBD-induced gut hypersensitivity. The lack of effect on naïve rats suggests a selective analgesic effect in the inflamed gut. Our results suggest that in the colitis model, TRPV1 channels are tonically active. Furthermore, our results emphasize the role of TRPV1-expressing nociceptive fibers in colitis-induced pain. These findings provide proof of concept for using charged activity blockers for the blockade of IBD-associated abdominal pain.


Here, we show that the selective silencing of a specific subtype of nociceptive neurons innervating the gut mitigates colitis-induced visceral hypersensitivity and pain. Our results provide a basis for developing effective and selective treatments for inflammatory bowel disease pain.


Asunto(s)
Capsaicina , Colitis , Colon , Lidocaína , Canales Catiónicos TRPV , Animales , Masculino , Ratas , Capsaicina/farmacología , Capsaicina/análogos & derivados , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/complicaciones , Colon/metabolismo , Colon/patología , Modelos Animales de Enfermedad , Lidocaína/farmacología , Lidocaína/análogos & derivados , Nociceptores/metabolismo , Ratas Sprague-Dawley , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/antagonistas & inhibidores , Dolor Visceral/etiología , Dolor Visceral/tratamiento farmacológico , Dolor Visceral/metabolismo
11.
Neurogastroenterol Motil ; 36(4): e14760, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38361164

RESUMEN

BACKGROUND: Chronic visceral hypersensitivity is closely associated with irritable bowel syndrome (IBS), a very common disorder which significantly impairs quality of life, characterized by abdominal pain, and distension. Imaging studies have found that IBS patients show higher metabolic activities and functional differences from normal controls in the anterior cingulate cortex (ACC), in response to visceral pain stimulation. Non-clinical data and clinical data suggest that medicinal products containing essential oils such as peppermint or caraway oil exert beneficial effects on IBS symptoms. METHODS: We assessed acute and long-term treatment effects of a mixture of peppermint and caraway essential oils (Menthacarin) on brain electrophysiological markers of gut pain sensitivity in two rat models of visceral hypersensitivity. KEY RESULTS: Chronic administration of corticosteroids and acute repeated mechanical hyperstimulation under anesthesia induced hyperalgesia and hypersensitivity, characterized by an increase in electrophysiological excitatory responses of ACC neurons to colorectal distension (CRD) and an increase in the proportion of neurons responding to otherwise subthreshold stimulation, respectively. Long-term, but not acute, oral administration of Menthacarin (60 mg kg-1 day-1) significantly reduced the net excitatory response to CRD in normally responsive control animals and counteracted the development of visceral hyperalgesia and hypersensitivity induced by repeated corticosterone administration and acute mechanical stimulation. CONCLUSIONS & INFERENCES: The present study shows that, using the CRD method, chronic Menthacarin administration at a clinically relevant dose attenuates the neuronal discharge associated with visceral pain stimuli in the rat ACC, particularly in models of hypersensitivity, suggesting a potential for treating exaggerated visceral pain sensitivity.


Asunto(s)
Síndrome del Colon Irritable , Aceites Volátiles , Dolor Visceral , Humanos , Ratas , Animales , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Síndrome del Colon Irritable/tratamiento farmacológico , Dolor Visceral/tratamiento farmacológico , Nocicepción , Calidad de Vida , Dolor Abdominal/inducido químicamente , Dolor Abdominal/tratamiento farmacológico
12.
Peptides ; 175: 171181, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38423212

RESUMEN

Thyrotropin-releasing hormone (TRH) acts centrally to exert pleiotropic actions independently from its endocrine function, including antinociceptive effects against somatic pain in rodents. Whether exogenous or endogenous activation of TRH signaling in the brain modulates visceral pain is unknown. Adult male Sprague-Dawley rats received an intracerebroventricular (ICV) injection of the stable TRH analog, RX-77368 (10, 30 and 100 ng/rat) or saline (5 µl) or were semi-restrained and exposed to cold (4°C) for 45 min. The visceromotor response (VMR) to graded phasic colorectal distensions (CRD) was monitored using non-invasive intracolonic pressure manometry. Naloxone (1 mg/kg) was injected subcutaneously 10 min before ICV RX-77368 or saline. Fecal pellet output was monitored for 1 h after ICV injection. RX-77368 ICV (10, 30 and 100 ng/rat) reduced significantly the VMR by 56.7%, 67.1% and 81.1% at 40 mmHg and by 30.3%, 58.9% and 87.4% at 60 mmHg respectively vs ICV saline. Naloxone reduced RX-77368 (30 and 100 ng, ICV) analgesic response by 51% and 28% at 40 mmHg and by 30% and 33% at 60 mmHg respectively, but had no effect per se. The visceral analgesia was mimicked by the acute exposure to cold. At the doses of 30 and 100 ng, ICV RX-77368 induced defecation within 30 min. These data established the antinociceptive action of RX-77368 injected ICV in a model of visceral pain induced by colonic distension through recruitment of both opioid and non-opioid dependent mechanisms.


Asunto(s)
Neoplasias Colorrectales , Ácido Pirrolidona Carboxílico/análogos & derivados , Hormona Liberadora de Tirotropina/análogos & derivados , Dolor Visceral , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Dolor Visceral/tratamiento farmacológico , Analgésicos/farmacología , Naloxona/farmacología
13.
Curr Pharm Biotechnol ; 25(13): 1632-1650, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38258770

RESUMEN

BACKGROUND: Visceral hypersensitivity (VH) is an overreaction of the gastrointestinal (GI) tract to various stimuli and is characterized by hyperalgesia and/or allodynia. VH contributes to the etiology of many GI dysfunctions, particularly irritable bowel syndrome (IBS). Although the exact mechanisms underlying VH are yet to be found, inflammation and oxidative stress, psychosocial factors, and sensorimotor alterations may play significant roles in it. OBJECTIVE: In this review, we provide an overview of VH and its pathophysiological function in GI disorders. Adverse effects of synthetic drugs may make herbal agents a good candidate for pain management. Therefore, in this review, we will discuss the efficacy of herbal agents in the management of VH with a focus on their anti-inflammatory and antioxidant potentials. METHODS: Data were extracted from clinical and animal studies published in English between 2004 and June, 2020, which were collected from PubMed, Google Scholar, Scopus, and Cochrane Library. RESULTS: Overall, Radix, Melissia, Glycyrrhizae, Mentha, and Liquorice were the most efficient herbals for VH management in IBS and dyspepsia, predominantly through modulation of the mRNA expression of transient receptor potential vanilloid type-1 (TRPV1) and suppression of 5- hydroxytryptamine 3 (5-HT3) or the serotonin receptors. CONCLUSION: Considering the positive effects of herbal formulations in VH management, further research on novel herbal and/or herbal/chemical preparations is warranted.


Asunto(s)
Enfermedades Gastrointestinales , Humanos , Animales , Enfermedades Gastrointestinales/tratamiento farmacológico , Preparaciones de Plantas/uso terapéutico , Preparaciones de Plantas/farmacología , Síndrome del Colon Irritable/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Dolor Visceral/tratamiento farmacológico , Canales Catiónicos TRPV/metabolismo
14.
BMJ Support Palliat Care ; 13(e3): e974-e976, 2024 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-37400161

RESUMEN

BACKGROUND: Visceral pain accounts for nearly 28% of cancer-related pain, and its effective management poses significant challenges. The diverse pathways of neurotransmission, neurotransmitters, channels, and receptors suggest the need for individualized analgesic therapy. Our objective is to explore a therapeutic alternative for managing malignant visceral pain in advanced cancer. CASES: In this report, we present two patients with malignant bowel obstruction and severe visceral pain, despite receiving opioid treatment, necessitating an alternative approach. Surgical interventions were considered but promptly ruled out. Paracentesis was performed as necessary. Pain management was initiated using a combination of opioids and co-analgesics. However, both patients required opioid dose escalation without achieving adequate pain control or tolerating the associated side effects. Consequently, a lidocaine infusion was administered to alleviate pain. OUTCOME: Following 24-48 hours of lidocaine infusion, both patients achieved satisfactory symptom control, enabling a reduction in opioid doses and improvement in intestinal transit. No side effects were reported during the treatment. DISCUSSION: Lidocaine infusions may be beneficial for pain management in patients with malignant bowel obstruction and visceral pain. The extent of pain control achieved in comparison to other therapeutics remains challenging to ascertain. We posit that lidocaine infusions, with their potential impact on visceral hypersensitivity, can enhance pain control and facilitate the recovery of bowel transit. Further studies are warranted to validate these findings.


Asunto(s)
Lidocaína , Dolor Visceral , Humanos , Analgésicos , Analgésicos Opioides/uso terapéutico , Lidocaína/uso terapéutico , Manejo del Dolor , Dolor Visceral/tratamiento farmacológico , Dolor Visceral/etiología
15.
Cannabis Cannabinoid Res ; 9(1): 3-11, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-37883662

RESUMEN

Cannabis and cannabis products are becoming increasingly popular options for symptom management of inflammatory bowel diseases, particularly abdominal pain. While anecdotal and patient reports suggest efficacy of these compounds for these conditions, clinical research has shown mixed results. To date, clinical research has focused primarily on delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is a ligand of classical cannabinoid receptors (CBRs). CBD is one of a large group of nonintoxicating cannabinoids (niCBs) that mediate their effects on both CBRs and through non-CBR mechanisms of action. Because they are not psychotropic, there is increasing interest and availability of niCBs. The numerous niCBs show potential to rectify abnormal intestinal motility as well as have anti-inflammatory and analgesic effects. The effects of niCBs are frequently not mediated by CBRs, but rather through actions on other targets, including transient receptor potential channels and voltage-gated ion channels. Additionally, evidence suggests that niCBs can be combined to increase their potency through what is termed the entourage effect. This review examines the pre-clinical data available surrounding these niCBs in treatment of abdominal pain with a focus on non-CBR mechanisms.


Asunto(s)
Cannabidiol , Cannabinoides , Cannabis , Alucinógenos , Dolor Visceral , Humanos , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Dolor Visceral/tratamiento farmacológico , Cannabidiol/farmacología , Dolor Abdominal/tratamiento farmacológico
16.
Br J Pharmacol ; 181(8): 1268-1289, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37990825

RESUMEN

BACKGROUND AND PURPOSE: Endomorphins have shown great promise as pharmaceutics for the treatment of pain. We have previously confirmed that novel endomorphin analogues CEMR-1 and CEMR-2 behaved as potent µ agonists and displayed potent antinociceptive activities at the supraspinal and peripheral levels. The present study was undertaken to evaluate the antinociceptive properties of CEMR-1 and CEMR-2 following intrathecal (i.t.) administration. Furthermore, their antinociceptive tolerance and opioid-like side effects were also determined. EXPERIMENTAL APPROACH: The spinal antinociceptive effects of CEMR-1 and CEMR-2 were determined in a series of pain models, including acute radiant heat paw withdrawal test, spared nerve injury-induced neuropathic pain, complete Freund's adjuvant-induced inflammatory pain, visceral pain and formalin pain. Antinociceptive tolerance was evaluated in radiant heat paw withdrawal test. KEY RESULTS: Spinal administration of CEMR-1 and CEMR-2 produced potent and prolonged antinociceptive effects in acute pain. CEMR-1 and CEMR-2 may produce their antinociception through distinct µ receptor subtypes. These two analogues also exhibited significant analgesic activities in neuropathic, inflammatory, visceral and formalin pain at the spinal level. It is noteworthy that CEMR-1 showed non-tolerance-forming analgesic properties, while CEMR-2 exhibited substantially reduced antinociceptive tolerance. Furthermore, both analogues displayed no or reduced side effects on conditioned place preference response, physical dependence, locomotor activity and gastrointestinal transit. CONCLUSIONS AND IMPLICATIONS: The present investigation demonstrated that CEMR-1 and CEMR-2 displayed potent and long-lasting antinociception with a favourable side effect profile at the spinal level. Therefore, CEMR-1 and CEMR-2 might serve as promising analgesic compounds with minimal opioid-like side effects.


Asunto(s)
Neuralgia , Dolor Visceral , Humanos , Analgésicos Opioides/farmacología , Analgésicos/farmacología , Analgésicos/uso terapéutico , Neuralgia/tratamiento farmacológico , Dolor Visceral/tratamiento farmacológico , Receptores Opioides mu/agonistas , Formaldehído/uso terapéutico
17.
Int J Mol Sci ; 24(19)2023 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-37833878

RESUMEN

5-fluorouracil (5-FU) is an antineoplastic drug used to treat colorectal cancer, but it causes, among other adverse effects, diarrhea and mucositis, as well as enteric neuropathy, as shown in experimental animals. It might also cause neuropathic pain and alterations in visceral sensitivity, but this has not been studied in either patients or experimental animals. Cannabinoids have antimotility and analgesic effects and may alleviate 5-FU-induced adverse effects. Our aim was to evaluate the effects of the cannabinoid agonist WIN 55,212-2 on neuropathic and visceral pain induced by a non-diarrheagenic dose of 5-FU. Male Wistar rats received a dose of 5-FU (150 mg/kg, ip) and gastrointestinal motility, colonic sensitivity, gut wall structure and tactile sensitivity were evaluated. WIN 55,212-2 (WIN) was administered to evaluate its effect on somatic (50-100 µg ipl; 1 mg/kg, ip) and visceral (1 mg/kg, ip) sensitivity. The cannabinoid tetrad was used to assess the central effects of WIN (1 mg/kg, ip). 5-FU decreased food intake and body weight gain, produced mucositis and thermal hyperalgesia, but these effects were reduced afterwards, and were not accompanied by diarrhea. Tactile mechanical allodynia was also evident and persisted for 15 days. Interestingly, it was alleviated by WIN. 5-FU tended to increase colonic sensitivity whereas WIN reduced the abdominal contractions induced by increasing intracolonic pressure in both control and 5-FU-treated animals. Importantly, the alleviating effects of WIN against those induced by 5-FU were not accompanied by any effect in the cannabinoid tetrad. The activation of the peripheral cannabinoid system may be useful to alleviate neuropathic and visceral pain associated with antitumoral treatment.


Asunto(s)
Cannabinoides , Mucositis , Neuralgia , Dolor Visceral , Humanos , Ratas , Masculino , Animales , Ratas Wistar , Agonistas de Receptores de Cannabinoides/uso terapéutico , Dolor Visceral/tratamiento farmacológico , Dolor Visceral/etiología , Mucositis/tratamiento farmacológico , Fluorouracilo/efectos adversos , Benzoxazinas/farmacología , Benzoxazinas/uso terapéutico , Neuralgia/tratamiento farmacológico , Neuralgia/inducido químicamente , Cannabinoides/farmacología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inducido químicamente , Diarrea/tratamiento farmacológico
18.
Int J Mol Sci ; 24(19)2023 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-37834289

RESUMEN

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


Asunto(s)
Colitis , Dolor Visceral , Humanos , Ratas , Animales , Acetilcarnitina/farmacología , Acetilcarnitina/uso terapéutico , Dolor Visceral/tratamiento farmacológico , Dolor Visceral/etiología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Colitis/inducido químicamente , Colitis/complicaciones , Colitis/tratamiento farmacológico , Neuroglía , Sistema Nervioso Central
19.
Mol Pain ; 19: 17448069231179118, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37347150

RESUMEN

BACKGROUND: Irritable bowel syndrome (IBS) is one of the typical representatives of chronic functional visceral pain that lacks effective treatment. Recently, attention has been given to the role of microglia in IBS, particularly the activation of spinal microglia and the subsequent release of Cathepsin S (Cat S), a proteolytic enzyme. However, the specific role of spinal Cat S in IBS remains to be elucidated. The purpose of this study is to investigate the mechanisms underlying the regulation of visceral hypersensitivity in IBS-like rats by Cat S. METHODS: An IBS-like rat model was developed, and visceral sensitivity was tested via the electromyographic (EMG) response to colorectal distention (CRD) and pain threshold. Western blot and immunofluorescence were used to examine the expressions of proteins. The effects of inhibitors or neutralizing antibodies on visceral pain and the downstream molecular expressions were detected. The open-field test was performed to evaluate locomotor activity and anxiety-like behaviors in rats. RESULTS: We discovered that spinal Cat S was upregulated and colocalized with microglia in IBS-like rats. Treatment with LY3000328, a selective inhibitor of Cat S, dose-dependently down-regulated EMG amplitude and Fractalkine (FKN) expression, indicating that Cat S regulated visceral hypersensitivity via activating FKN in IBS-like rats. Furthermore, the expressions of FKN, CX3CR1, and p-p38 MAPK were elevated in IBS-like rats whereas inhibition of these molecules could alleviate visceral pain. Moreover, pharmacological inhibitor experiments suggested the activation of CX3CR1 by FKN facilitated p38 MAPK phosphorylation, which in turn promoted Cat S expression in IBS-like rats. CONCLUSIONS: Neonatal adverse stimulation might enhance the expression of spinal microglial Cat S, thereby activating the FKN/CX3CR1/p38 MAPK pathway and lead to visceral hypersensitivity in IBS-like rats. As a selective inhibitor of Cat S, LY3000328 could become a potential therapeutic option for IBS.


Asunto(s)
Dolor Crónico , Síndrome del Colon Irritable , Dolor Visceral , Ratas , Animales , Dolor Visceral/tratamiento farmacológico , Quimiocina CX3CL1/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Modelos Animales de Enfermedad , Receptor 1 de Quimiocinas CX3C/metabolismo
20.
J Neurosci Res ; 101(10): 1555-1571, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37331003

RESUMEN

The serotonergic 5-HT1A receptors are implicated in the central mechanisms of visceral pain, but their role in these processes is controversial. Considering existing evidences for organic inflammation-triggered neuroplastic changes in the brain serotonergic circuitry, the ambiguous contribution of 5-HT1A receptors to supraspinal control of visceral pain in normal and post-inflammatory conditions can be assumed. In this study performed on male Wistar rats, we used microelectrode recording of the caudal ventrolateral medulla (CVLM) neuron responses to colorectal distension (CRD) and electromyography recording of CRD-evoked visceromotor reactions (VMRs) to evaluate post-colitis changes in the effects of 5-HT1A agonist buspirone on supraspinal visceral nociceptive transmission. In rats recovered from trinitrobenzene sulfonic acid colitis, the CRD-induced CVLM neuronal excitation and VMRs were increased compared with those in healthy animals, revealing post-inflammatory intestinal hypersensitivity. Intravenous buspirone (2 and 4 mg/kg) under urethane anesthesia dose-dependently suppressed CVLM excitatory neuron responses to noxious CRD in healthy rats, but caused dose-independent increase in the already enhanced nociceptive activation of CVLM neurons in post-colitis animals, losing also its normally occurring faciliatory effect on CRD-evoked inhibitory medullary neurotransmission and suppressive action on hemodynamic reactions to CRD. In line with this, subcutaneous injection of buspirone (2 mg/kg) in conscious rats, which attenuated CRD-induced VMRs in controls, further increased VMRs in hypersensitive animals. The data obtained indicate a shift from anti- to pronociceptive contribution of 5-HT1A-dependent mechanisms to supraspinal transmission of visceral nociception in intestinal hypersensitivity conditions, arguing for the disutility of buspirone and possibly other 5-HT1A agonists for relieving post-inflammatory abdominal pain.


Asunto(s)
Colitis , Dolor Visceral , Masculino , Ratas , Animales , Receptor de Serotonina 5-HT1A , Buspirona/farmacología , Ratas Wistar , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Dolor Visceral/tratamiento farmacológico , Dolor Abdominal
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...