RESUMEN
Melilotus officinalis is known to contain several types of secondary metabolites. In contrast, the carotenoid composition of this medicinal plant has not been investigated, although it may also contribute to the biological activities of the drug, such as anti-inflammatory effects. Therefore, this study focuses on the isolation and identification of carotenoids from Meliloti herba and on the effect of isolated (all-E)-lutein 5,6-epoxide on primary sensory neurons and macrophages involved in nociception, as well as neurogenic and non-neurogenic inflammatory processes. The composition of the plant extracts was analyzed by high performance liquid chromatography (HPLC). The main carotenoid was isolated by column liquid chromatography (CLC) and identified by MS and NMR. The effect of water-soluble lutein 5,6-epoxide-RAMEB (randomly methylated-ß-cyclodextrin) was investigated on Ca2+-influx in rat primary sensory neurons induced by the activation of the transient receptor potential ankyrin 1 receptor agonist to mustard-oil and on endotoxin-induced IL-1ß release from isolated mouse peritoneal macrophages. (all-E)-Lutein 5,6-epoxide significantly decreased the percent of responsive primary sensory neurons compared to the vehicle-treated stimulated control. Furthermore, endotoxin-evoked IL-1ß release from macrophages was significantly decreased by 100 µM lutein 5,6-epoxide compared to the vehicle-treated control. The water-soluble form of lutein 5,6-epoxide-RAMEB decreases the activation of primary sensory neurons and macrophages, which opens perspectives for its analgesic and anti-inflammatory applications.
Asunto(s)
Luteína/análogos & derivados , Macrófagos/efectos de los fármacos , Melilotus/química , Células Receptoras Sensoriales/efectos de los fármacos , Animales , Luteína/análisis , Luteína/aislamiento & purificación , Luteína/farmacología , Macrófagos/citología , Ratones , Ratas , Células Receptoras Sensoriales/citologíaRESUMEN
Thyme (TO), cinnamon (CO), and Ceylon type lemongrass (LO) essential oils (EOs) are commonly used for inhalation. However, their effects and mechanisms on inflammatory processes are not well-documented, and the number of in vivo data that would be important to determine their potential benefits or risks is low. Therefore, we analyzed the chemical composition and investigated the activity of TO, CO, and LO on airway functions and inflammatory parameters in an acute pneumonitis mouse model. The components of commercially available EOs were measured by gas chromatography-mass spectrometry. Airway inflammation was induced by intratracheal endotoxin administration in mice. EOs were inhaled during the experiments. Airway function and hyperresponsiveness were determined by unrestrained whole-body plethysmography on conscious animals. Myeloperoxidase (MPO) activity was measured by spectrophotometry from lung tissue homogenates, from which semiquantitative histopathological scores were assessed. The main components of TO, CO, and LO were thymol, cinnamaldehyde, and citronellal, respectively. We provide here the first evidence that TO and CO reduce inflammatory airway hyperresponsiveness and certain cellular inflammatory parameters, so they can potentially be considered as adjuvant treatments in respiratory inflammatory conditions. In contrast, Ceylon type LO inhalation might have an irritant effect (e.g., increased airway hyperresponsiveness and MPO activity) on the inflamed airways, and therefore should be avoided.
Asunto(s)
Antiinflamatorios/farmacología , Endotoxinas/efectos adversos , Aceites Volátiles/farmacología , Aceites de Plantas/farmacología , Thymus (Planta)/química , Animales , Antiinflamatorios/química , Biomarcadores , Modelos Animales de Enfermedad , Femenino , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inflamación/patología , Pulmón/efectos de los fármacos , Pulmón/patología , Ratones , Aceites Volátiles/química , Aceites de Plantas/química , Enfermedades Respiratorias/tratamiento farmacológico , Enfermedades Respiratorias/etiología , Enfermedades Respiratorias/patologíaRESUMEN
Semicarbazide-sensitive amine oxidase (SSAO) catalyses oxidative deamination of primary amines. Since there is no data about its function in pain and arthritis mechanisms, we investigated the effects of our novel SSAO inhibitor SzV-1287 in chronic mouse models of joint inflammation. Effects of SzV-1287 (20 mg/kg i.p./day) were investigated in the K/BxN serum-transfer and complete Freund's adjuvant (CFA)-evoked active immunization models compared to the reference SSAO inhibitor LJP-1207. Mechanonociception was assessed by aesthesiometry, oedema by plethysmometry, clinical severity by scoring, joint function by grid test, myeloperoxidase activity by luminescence, vascular leakage by fluorescence in vivo imaging, histopathological changes by semiquantitative evaluation, and cytokines by Luminex assay. SzV-1287 significantly inhibited hyperalgesia and oedema in both models. Plasma leakage and keratinocyte chemoattractant production in the tibiotarsal joint, but not myeloperoxidase activity was significantly reduced by SzV-1287 in K/BxN-arthritis. SzV-1287 did not influence vascular and cellular mechanisms in CFA-arthritis, but significantly decreased histopathological alterations. There was no difference in the anti-hyperalgesic and anti-inflammatory actions of SzV-1287 and LJP-1207, but only SzV-1287 decreased CFA-induced tissue damage. Unlike SzV-1287, LJP-1207 induced cartilage destruction, which was confirmed in vitro. SzV-1287 exerts potent analgesic and anti-inflammatory actions in chronic arthritis models of distinct mechanisms, without inducing cartilage damage.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Analgésicos no Narcóticos/uso terapéutico , Antiinflamatorios/uso terapéutico , Artritis/tratamiento farmacológico , Hidrazinas/uso terapéutico , Articulaciones/patología , Oxazoles/uso terapéutico , Oximas/uso terapéutico , Animales , Células Cultivadas , Enfermedad Crónica , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Adyuvante de Freund/inmunología , Humanos , Hidrazinas/farmacología , Articulaciones/efectos de los fármacos , Ratones , Ratones Endogámicos , Ratones Transgénicos , Oxazoles/farmacología , Oximas/farmacologíaRESUMEN
OBJECTIVE, DESIGN: Mast cell tryptase (MCT) is elevated in arthritic joints, but its direct effects are not known. Here, we investigated MCT-evoked acute inflammatory and nociceptive mechanisms with behavioural, in vivo imaging and immunological techniques. MATERIAL AND SUBJECTS: Neurogenic inflammation involving capsaicin-sensitive afferents, transient receptor potential vanilloid 1 receptor (TRPV1), substance P (SP), neurokinin A (NKA) and their NK1 tachykinin receptor were studied using gene-deleted mice compared to C57Bl/6 wildtypes (n = 5-8/group). TREATMENT: MCT was administered intraarticularly or topically (20 µl, 12 µg/ml). Capsaicin-sensitive afferents were defunctionalized with the TRPV1 agonist resiniferatoxin (RTX; 30-70-100 µg/kg s.c. pretreatment). METHODS: Knee diameter was measured with a caliper, synovial perfusion with laser Doppler imaging, mechanonociception with aesthesiometry and weight distribution with incapacitance tester over 6 h. Cytokines and neuropeptides were determined with immunoassays. RESULTS: MCT induced synovial vasodilatation, oedema, impaired weight distribution and mechanical hyperalgesia, but cytokine or neuropeptide levels were not altered at the 6-h timepoint. Hyperaemia was reduced in RTX-treated and TRPV1-deleted animals, and oedema was absent in NK1-deficient mice. Hyperalgesia was decreased in SP/NKA- and NK1-deficient mice, weight bearing impairment in RTX-pretreated, TRPV1- and NK1-deficient animals. CONCLUSIONS: MCT evokes synovial hyperaemia, oedema, hyperalgesia and spontaneous pain. Capsaicin-sensitive afferents and TRPV1 receptors are essential for vasodilatation, while tachykinins mediate oedema and pain.
Asunto(s)
Artritis/inducido químicamente , Edema/inducido químicamente , Hiperalgesia/inducido químicamente , Inflamación Neurogénica/inducido químicamente , Dolor/inducido químicamente , Triptasas , Animales , Artritis/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Capsaicina , Citocinas/metabolismo , Edema/metabolismo , Edema/patología , Hiperalgesia/metabolismo , Hiperalgesia/patología , Articulación de la Rodilla/metabolismo , Articulación de la Rodilla/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Inflamación Neurogénica/metabolismo , Inflamación Neurogénica/patología , Dolor/metabolismo , Dolor/patología , Precursores de Proteínas/genética , Receptor PAR-2/metabolismo , Receptores de Neuroquinina-1/genética , Sustancia P/metabolismo , Canales Catiónicos TRPV/genética , Taquicininas/genética , TactoRESUMEN
Neurogenic inflammation mediated by peptidergic sensory nerves has a crucial impact on the pathogenesis of various joint diseases. Galanin is a regulatory sensory neuropeptide, which has been shown to attenuate neurogenic inflammation, modulate neutrophil activation, and be involved in the development of adjuvant arthritis, but our current understanding about its targets and physiological importance is incomplete. Among the receptors of galanin (GAL1-3), GAL3 has been found to be the most abundantly expressed in the vasculature and on the surface of some immune cells. However, since there are minimal in vivo data on the role of GAL3 in joint diseases, we analyzed its involvement in different inflammatory mechanisms of the K/BxN serum transfer-model of autoimmune arthritis employing GAL 3 gene-deficient mice. After arthritis induction, GAL3 knockouts demonstrated increased clinical disease severity and earlier hindlimb edema than wild types. Vascular hyperpermeability determined by in vivo fluorescence imaging was also elevated compared to the wild-type controls. However, neutrophil accumulation detected by in vivo luminescence imaging or arthritic mechanical hyperalgesia was not altered by the lack of the GAL3 receptor. Our findings suggest that GAL3 has anti-inflammatory properties in joints by inhibiting vascular hyperpermeability and consequent edema formation.
Asunto(s)
Artritis/metabolismo , Enfermedades Autoinmunes/metabolismo , Receptor de Galanina Tipo 3/genética , Animales , Artritis/genética , Artritis/patología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/patología , Permeabilidad Capilar , Edema/metabolismo , Endotelio Vascular/metabolismo , Miembro Posterior/patología , Masculino , Ratones , Neutrófilos/metabolismo , Receptor de Galanina Tipo 3/deficienciaRESUMEN
BACKGROUND: Capsaicin, which is the major pungent principle in chili peppers, is able to induce satiety and reduce caloric intake. The exact mechanism behind this satiating effect is still unknown. We hypothesized that capsaicin induces satiety through the release of gastrointestinal peptides, such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), from enteroendocrine cells in the small intestine. OBJECTIVE: We investigate the effects of an intraduodenal capsaicin infusion (1.5 mg pure capsaicin) in healthy volunteers on hunger, satiety, and gastrointestinal symptoms and the release of GLP-1 and PYY. DESIGN: Thirteen participants (7 women) [mean ± SEM age: 21.5 ± 0.6 y; body mass index (in kg/m(2)): 22.8 ± 0.6] participated in this single-blind, randomized, placebo-controlled crossover study with 2 different treatments. During test days, an intraduodenal infusion of either capsaicin or a placebo (physiologic saline) was performed with the use of a nasoduodenal catheter over a period of 30 min. Visual analog scale scores were used to measure hunger, satiety, and gastrointestinal symptoms. Blood samples were drawn at regular intervals for GLP-1 and PYY. Gallbladder volumes were measured with the use of real-time ultrasonography. RESULTS: The intraduodenal capsaicin infusion significantly increased satiety (P-treatment effect < 0.05) but also resulted in an increase in the gastrointestinal symptoms pain (P-treatment × time interaction < 0.0005), burning sensation (P-treatment × time interaction < 0.0001), nausea (P-treatment × time interaction < 0.05), and bloating (P-treatment × time interaction < 0.001) compared with the effects of the placebo infusion. Satiety scores had a positive correlation with all gastrointestinal symptoms. No differences in GLP-1 and PYY concentrations and gallbladder volumes were observed after the capsaicin infusion compared with after the placebo infusion. CONCLUSIONS: An intraduodenal infusion of capsaicin significantly increases satiety but does not affect plasma concentrations of GLP-1 and PYY. Rather, the effect on satiety seems related to gastrointestinal stress as shown by the associations with pain, burning sensation, nausea, and bloating scores. This trial was registered at clinicaltrials.gov as NCT01667523.
Asunto(s)
Depresores del Apetito/efectos adversos , Capsaicina/efectos adversos , Suplementos Dietéticos/efectos adversos , Enteritis/etiología , Péptido 1 Similar al Glucagón/metabolismo , Péptido YY/metabolismo , Respuesta de Saciedad , Dolor Abdominal/etiología , Adulto , Depresores del Apetito/administración & dosificación , Biomarcadores , Capsaicina/administración & dosificación , Estudios Cruzados , Enteritis/metabolismo , Enteritis/patología , Enteritis/fisiopatología , Femenino , Vesícula Biliar/diagnóstico por imagen , Vesícula Biliar/metabolismo , Vesícula Biliar/patología , Péptido 1 Similar al Glucagón/sangre , Humanos , Intubación Gastrointestinal , Náusea/etiología , Tamaño de los Órganos , Dimensión del Dolor , Péptido YY/sangre , Método Simple Ciego , Ultrasonografía , Adulto JovenRESUMEN
BACKGROUND: The transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable cation channel that is expressed on capsaicin-sensitive sensory neurons, endothelial and inflammatory cells. It is activated by a variety of inflammatory mediators, such as methylglyoxal, formaldehyde and hydrogen sulphide. Since only few data are available about the role of TRPA1 in arthritis and related pain, we investigated its involvement in inflammation models of different mechanisms. METHODS: Chronic arthritis was induced by complete Freund's adjuvant (CFA), knee osteoarthritis by monosodium iodoacetate (MIA) in TRPA1 knockout (KO) mice and C57Bl/6 wildtype mice. For comparison, carrageenan- and CFA-evoked acute paw and knee inflammatory changes were investigated. Thermonociception was determined on a hot plate, cold tolerance in icy water, mechanonociception by aesthesiometry, paw volume by plethysmometry, knee diameter by micrometry, weight distribution with incapacitance tester, neutrophil myeloperoxidase activity and vascular leakage by in vivo optical imaging, and histopathological alterations by semiquantitative scoring. RESULTS: CFA-induced chronic mechanical hypersensitivity, tibiotarsal joint swelling and histopathological alterations, as well as myeloperoxidase activity in the early phase (day 2), and vascular leakage in the later stage (day 7), were significantly reduced in TRPA1 KO mice. Heat and cold sensitivities did not change in this model. Although in TRPA1 KO animals MIA-evoked knee swelling and histopathological destruction were not altered, hypersensitivity and impaired weight bearing on the osteoarthritic limb were significantly decreased. In contrast, carrageenan- and CFA-induced acute inflammation and pain behaviours were not modified by TRPA1 deletion. CONCLUSIONS: TRPA1 has an important role in chronic arthritis/osteoarthritis and related pain behaviours in the mouse. Therefore, it might be a promising target for novel analgesic/anti-inflammatory drugs.
Asunto(s)
Artritis Experimental/metabolismo , Artritis Experimental/patología , Canales de Potencial de Receptor Transitorio/deficiencia , Animales , Enfermedad Crónica , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Canal Catiónico TRPA1RESUMEN
Mechanisms of the potent anti-inflammatory actions of carotenoids are unknown. Since carotenoids are incorporated into membranes, they might modulate transient receptor potential ankyrin 1 and vanilloid 1 (TRPA1 and TRPV1) activation predominantly on peptidergic sensory nerves. We therefore investigated the effects of three carotenoids (ß-carotene, lutein and lycopene) on cutaneous neurogenic inflammation. Acute neurogenic edema and inflammatory cell recruitment were induced by smearing the TRPA1 agonist mustard oil (5%) or the TRPV1 activator capsaicin (2.5%) on the mouse ear. Ear thickness was then determined by micrometry, microcirculation by laser Doppler imaging and neutrophil accumulation by histopathology and spectrophotometric determination of myeloperoxidase activity. The effects of lutein on the stimulatory action of the TRPA1 agonist mustard oil were also tested on the guinea-pig small intestine, in isolated organ experiments. Mustard oil evoked 50-55% ear edema and granulocyte influx, as shown by histology and myeloperoxidase activity. Swelling was significantly reduced between 2 and 4 h after administration of lutein or ß-carotene (100 mg/kg subcutane three times during 24 h). Lutein also decreased neutrophil accumulation induced by TRPA1 activation, but did not affect mustard oil-evoked intestinal contraction. Lycopene had no effect on any of these parameters. None of the three carotenoids altered capsaicin-evoked inflammation. It is proposed that the dihydroxycarotenoid lutein selectively inhibits TRPA1 activation and consequent neurogenic inflammation, possibly by modulating lipid rafts.
Asunto(s)
Carotenoides/farmacología , Inflamación Neurogénica/tratamiento farmacológico , Piel/efectos de los fármacos , Canales Catiónicos TRPV/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Animales , Capsaicina/farmacología , Carotenoides/uso terapéutico , Femenino , Cobayas , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patología , Masculino , Ratones , Planta de la Mostaza , Inflamación Neurogénica/metabolismo , Aceites de Plantas/farmacología , Piel/metabolismo , Piel/patología , Canal Catiónico TRPA1 , Canales Catiónicos TRPV/agonistas , Canales de Potencial de Receptor Transitorio/agonistasRESUMEN
The aim of the present study was to evaluate the therapeutic potential of local capsaicinoid (EMSPOMA(®) cream) treatment on chronic low back pain in patients with degenerative spine diseases and to investigate the possible mechanism of action of the therapy. The qualitative and quantitative analyses of capsaicinoids in EMSPOMA(®) cream were performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In the clinical study 20 patients with degenerative spine diseases were involved in a self-controlled examination. During the 21 day therapy they received 30 min daily treatment with capsaicinoid (EMSPOMA(®)) cream to the lumbar region of the back. The pain (VASs, Oswestry Disability Index) and the mobility of the lumbar region of the spine (Schober's, Domján's L and R test) were detected at baseline and at the end of the 1st, 2nd and 3rd weeks. The plasma level of somatostatin-like immunoreactivity (SST-LI) was measured by radioimmunoassay (RIA) before and after the treatment on the first and the last day of the therapy. Nonivamide (0.01%) was identified as the only capsaicinoid molecule in the cream. In the clinical study the 21 day local nonivamide treatment reduced the pain sensation. Oswestry Disability Index decreased from 39 ± 3.9% to 32.5 ± 4.4%. VASs showed 37.29%-59.51% improvement. In the plasma level of SST-LI threefold elevation was observed after the first nonivamide treatment. We conclude that nonivamide treatment exerts analgesic action in chronic low back pain and causes the release of the antinociceptive and anti-inflammatory neuropeptide somatostatin which may play pivotal role in the pain-relieving effect.
Asunto(s)
Analgésicos/administración & dosificación , Capsaicina/análogos & derivados , Dolor de la Región Lumbar/tratamiento farmacológico , Somatostatina/sangre , Administración Cutánea , Anciano , Capsaicina/administración & dosificación , Femenino , Humanos , Dolor de la Región Lumbar/etiología , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Enfermedades de la Médula Espinal/complicacionesRESUMEN
Previous studies showed comorbidity of some ocular, enteral, and affective symptoms comprising irritable eye syndrome. Aims of the present study were to learn more about the pathogenic mechanisms of this syndrome and to evaluate benefits of food supplements on these disorders. In in vitro assay, Lactobacillus acidophilus lysate inhibited interleukin (IL)-1ß and tumor necrosis factor (TNF)-α generation of lipopolysaccharide (LPS)-stimulated macrophages in dose- and size-dependent manner. For a prospective, open-label phase I/II controlled clinical trial, 40 subjects affected by ocular dysesthesia and hyperesthesia and comorbid enteral and anxiety-depression symptoms were randomly assigned either into the treated group, which received a composition containing probiotic lysate, vitamins A, B, and D and omega 3 fatty acids, or into the control group, which received vitamins and omega 3 fatty acids. For reference, 20 age- and sex-matched healthy subjects were also selected. White blood count (WBC) and lymphocyte and monocyte counts, as well as IL-6 and TNF-α levels, were significantly above the reference levels in both treated and control groups. After 8 weeks, WBC and lymphocyte and monocyte counts, and cytokine levels significantly decreased, and ocular, enteral, and anxiety-depression symptoms significantly improved in the treated group as compared to the control group. This proof-of-concept study suggested that subclinical inflammation may be a common mechanism connecting ocular, enteral, and anxiety/depression symptoms, and supplements affecting dysbiosis may be a new approach to treating this syndrome.
Asunto(s)
Ácidos Grasos Omega-3/administración & dosificación , Queratitis/inmunología , Queratitis/terapia , Probióticos/uso terapéutico , Vitaminas/administración & dosificación , Adulto , Animales , Aceite de Hígado de Bacalao/administración & dosificación , Estreñimiento/complicaciones , Depresión/complicaciones , Diarrea/complicaciones , Femenino , Humanos , Interleucina-1beta/inmunología , Interleucina-6/inmunología , Queratitis/complicaciones , Lactobacillus acidophilus , Macrófagos/inmunología , Masculino , Ratones Endogámicos , Persona de Mediana Edad , Neuroinmunomodulación/inmunología , Parestesia/inmunología , Parestesia/terapia , Estudios Prospectivos , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with widespread occurrence in the nervous system and peripheral organs, including the mammary gland. Previously, we have shown that PACAP38 is present in the human milk at higher levels than in respective blood samples. However, it is not known how PACAP levels and the expression of PAC1 receptor change during lactation. Therefore, the aim of our study was to investigate PACAP38-like immunoreactivity (PACAP38-LI) in human colostrums and transitional and mature milk during lactation and to compare the expression of PAC1 receptors in lactating and non-lactating mammary glands. We found that PACAP38-LI was significantly higher in human colostrum samples than in the transitional and mature milk. PACAP38-LI did not show any significant changes within the first 10-month period of lactation, but a significant increase was observed thereafter, up to the examined 17th month. Weak expression of PAC1 receptors was detected in non-lactating sheep and human mammary glands, but a significant increase was observed in the lactating sheep samples. In summary, the present study is the first to show changes of PACAP levels in human milk during lactation. The presence of PACAP in the milk suggests a potential role in the development of newborn, while the increased expressions of PAC1 receptors on lactating breast may indicate a PACAP38/PAC1 interaction in the mammary gland during lactation.
Asunto(s)
Mama/química , Calostro/química , Lactancia/fisiología , Glándulas Mamarias Animales/química , Leche Humana/química , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/análisis , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/análisis , Oveja Doméstica/fisiología , Animales , Mama/fisiología , Femenino , Regulación del Desarrollo de la Expresión Génica , Humanos , Glándulas Mamarias Animales/fisiología , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/biosíntesis , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/genética , Especificidad de la EspecieRESUMEN
The transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel localized on a subset of primary sensory neurons and can be activated by a wide range of stimuli. The present study investigated the role of this receptor in chronic arthritis evoked by complete Freund's adjuvant (CFA) using TRPV1 receptor gene-deleted (TRPV1-/-) mice and wild-type counterparts (TRPV1+/+). In TRPV1+/+ mice, CFA injected intraplantarly into the left hindpaw and the root of the tail induced swelling of the injected and contralateral paws up to 130 and 28%, respectively, measured by plethysmometry throughout 18 days. Mechanonociceptive threshold measured with dynamic plantar aesthesiometry was decreased by 50 and 18% on the injected and contralateral paws, respectively. Histological examination and scoring of the tibiotarsal joints revealed marked arthritic changes in wild-type mice. In TRPV1-/- animals edema, histological score and mechanical allodynia were significantly smaller. Daily treatment with the lipoxygenase inhibitor nordihydroguaretic acid (NDGA), the cyclooxygenase inhibitor indomethacin, the bradykinin B2 receptor antagonist HOE-140 [D-arginyl-L-arginyl-L-prolyl-trans-4-hydroxy-L-prolylglycyl-3-(2-thyenyl)-L-alanyl-L-seryl-D-1,2,2,4-tetrahydro-3-isoquinolinecarbonyl-L-(2a,3b,7ab)-octahydro-1H-indole-2-carbonyl-L-arginine], or the B1 receptor antagonist desArgHOE-140 [D-arginyl-L-arginyl-L-prolyl-trans-4-hydroxy-L-prolylglycyl-3-(2-thyenyl)-L-alanyl-L-seryl-D-1,2,2,4-tetrahydro-3-isoquinolinecarbonyl-L-(2a,3b,7ab)-octahydro-1H-indole-2-carbonyl] was performed to reveal what mediators might activate TRPV1. NDGA significantly inhibited edema, hyperalgesia, and arthritis score in TRPV1+/+, but not in TRPV1-/- mice. The effect of indomethacin was markedly smaller in knockouts. In TRPV1+/+ animals, HOE-140, but not desArgHOE-140, inhibited arthritis, whereas in TRPV1-/- mice, HOE-140 produced limited effect. Thus, whereas bradykinin and lipoxygenase products seem to act exclusively via TRPV1 activation, prostanoids do not, or at least only partially, to enhance murine experimental arthritis and related hyperalgesia.