RESUMEN
ABSTRACT: Primary headache conditions are frequently associated with multiple sclerosis (MS), but the mechanism that triggers or worsens headaches in patients with MS is poorly understood. We previously showed that the proalgesic transient receptor potential ankyrin 1 (TRPA1) mediates hind paw mechanical and cold allodynia in a relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) model in mice. Here, we investigated the development of periorbital mechanical allodynia (PMA) in RR-EAE, a hallmark of headache, and if TRPA1 contributed to this response. RR-EAE induction by injection of the myelin oligodendrocyte peptide fragment35-55 (MOG35-55) and Quillaja A adjuvant (Quil A) in C57BL/6J female mice elicited a delayed and sustained PMA. The PMA at day 35 after induction was reduced by the calcitonin gene-related peptide receptor antagonist (olcegepant) and the serotonin 5-HT1B/D receptor agonist (sumatriptan), 2 known antimigraine agents. Genetic deletion or pharmacological blockade of TRPA1 attenuated PMA associated with RR-EAE. The levels of oxidative stress biomarkers (4-hydroxynonenal and hydrogen peroxide, known TRPA1 endogenous agonists) and superoxide dismutase and NADPH oxidase activities were increased in the trigeminal ganglion of RR-EAE mice. Besides, the treatment with antioxidants (apocynin or α-lipoic acid) attenuated PMA. Thus, the results of this study indicate that TRPA1, presumably activated by endogenous agonists, evokes PMA in a mouse model of relapsing-remitting MS.
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Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Animales , Ancirinas , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/complicaciones , Femenino , Cefalea/complicaciones , Hiperalgesia/complicaciones , Hiperalgesia/etiología , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Canal Catiónico TRPA1/genéticaRESUMEN
Complex regional pain syndrome type-I (CRPS-I) is a chronic painful condition resulting from trauma. Bradykinin (BK) is an important inflammatory mediator required in acute and chronic pain response. The objective of this study was to evaluate the association between BK receptors (B1 and B2) and chronic post-ischaemia pain (CPIP) development in mice, a widely accepted CRPS-I model. We assessed mechanical and cold allodynia, and paw oedema in male and female Swiss mice exposed to the CPIP model. Upon induction, the animals were treated with BKR antagonists (HOE-140 and DALBK); BKR agonists (Tyr-BK and DABK); antisense oligonucleotides targeting B1 and B2 and captopril by different routes in the model (7, 14 and 21 days post-induction). Here, we demonstrated that treatment with BKR antagonists, by intraperitoneal (i.p.), intraplantar (i.pl.), and intrathecal (i.t.) routes, mitigated CPIP-induced mechanical allodynia and oedematogenic response, but not cold allodynia. On the other hand, i.pl. administration of BKR agonists exacerbated pain response. Moreover, a single treatment with captopril significantly reversed the anti-allodynic effect of BKR antagonists. In turn, the inhibition of BKRs gene expression in the spinal cord inhibited the nociceptive behaviour in the 14th post-induction. The results of the present study suggest the participation of BKRs in the development and maintenance of chronic pain associated with the CPIP model, possibly linking them to CRPS-I pathogenesis.
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Dolor Crónico/etiología , Dolor Crónico/metabolismo , Isquemia/complicaciones , Receptores de Bradiquinina/metabolismo , Animales , Antagonistas de los Receptores de Bradiquinina/farmacología , Inhibidores de la Colinesterasa/farmacología , Dolor Crónico/genética , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Hiperalgesia/complicaciones , Masculino , Ratones , Nocicepción/efectos de los fármacos , Receptores de Bradiquinina/genética , Médula Espinal/patologíaRESUMEN
Inflammatory dermatoses are prevalent worldwide, with impacts on the quality of life of patients and their families. The aim of this study was to determine the anti-inflammatory effects of Achyrocline satureioides oily extracts and nanocapsules on the skin using a mouse model of irritant contact dermatitis induced by croton oil, and a skin inflammation model induced by ultraviolet B (UVB) radiation. The mice were treated with 15 mg/ear oily extract (HG-OLAS) or nanocapsules (HG-NCAS) of A. satureioides incorporated into Carbopol® 940 hydrogels. We found that HG-OLAS and HG-NCAS formulations reduced ear edema in croton oil-induced lesions with maximum inhibitions of 54±7% and 74±3%, respectively. HG-OLAS and HG-NCAS formulations decreased ear edema induced by UVB radiation (0.5 J/cm2), with maximum inhibitions of 68±6% and 76±2% compared to the UVB radiation group, respectively. HG-OLAS and HG-NCAS modulated myeloperoxidase (MPO) activity after croton oil induction. Furthermore, croton oil and UVB radiation for 6 and 24 h, respectively, stimulated polymorphonuclear cells infiltration. The topical treatments reduced inflammatory processes, as shown by histological analysis. Together, the data suggest that topical application of A. satureioides oily extracts and nanocapsules produced antiedematogenic and anti-inflammatory effects. They constitute a compelling alternative for treatment of skin injuries.
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Achyrocline , Dermatitis por Contacto , Nanocápsulas , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Dermatitis por Contacto/tratamiento farmacológico , Edema/tratamiento farmacológico , Humanos , Hidrogeles , Irritantes/uso terapéutico , Nanocápsulas/uso terapéutico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Calidad de VidaRESUMEN
The thermal, physical, and morphological properties of diphenhydraminium ibuprofenate ([DIP][IBU]) adsorbed onto mesoporous silica (SiO2-60â¯Å and SiO2-90â¯Å) from solution were determined. The thermal, physical, and morphological properties of [DIP][IBU] supported on silica were determined. The adsorption of [DIP][IBU] on the pores and surface of silica was proven by N2 adsorption/desorption isotherms. Additionally, release profiles were determined for all systems, and the antinociceptive activity of neat [DIP][IBU] and [DIP][IBU] supported on silica were determined. The interaction of [DIP][IBU] and silica was dependent on pore size, with the formation of a [DIP][IBU] monolayer on SiO2-60 and a multilayer on SiO2-90. The release profile was sustained and slow and dependent on the pore size of the silica, in which the smaller the pore size, the faster the release. The nociceptive evaluation showed that [DIP][IBU] presents a greater (99.21⯱â¯0.85%) antinociceptive effect than the ibuprofen (46⯱â¯4.3%). Additionally, [DIP][IBU] on SiO2-60 (90⯱â¯5.8%) had a greater antinociceptive effect than on SiO2-90 (73⯱â¯13.2%), which indicates that in vivo tests are in accordance with the in vitro experiments.
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Analgésicos , Ibuprofeno , Dolor/tratamiento farmacológico , Dióxido de Silicio , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Evaluación Preclínica de Medicamentos , Ibuprofeno/análogos & derivados , Ibuprofeno/química , Ibuprofeno/farmacocinética , Ibuprofeno/farmacología , Masculino , Ratones , Dolor/metabolismo , Dolor/fisiopatología , Porosidad , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Dióxido de Silicio/farmacologíaRESUMEN
This study aimed to investigate the feasibility of producing semisolid formulations based on nanocapsule suspensions containing the association of the coenzyme Q10 and vitamin E acetate by adding gellan gum (2%) to the suspensions. Furthermore, we studied their application as an alternative for the treatment of inflammation induced by ultraviolet B (UVB) radiation. For this, an animal model of injury induced by UVB-radiation was employed. All semisolids presented pH close to 5.5, drug content above 95% and mean diameter on the nanometric range, after redispersion in water. Besides, the semisolids presented non-Newtonian flow with pseudoplastic behavior and suitable spreadability factor values. The results also showed that the semisolid containing coenzyme Q10-loaded nanocapsules with higher vitamin E acetate concentration reduced in 73±8% the UVB radiation-induced ear edema. Moreover, all formulations tested were able to reduce inflammation parameters evaluated through MPO activity and histological procedure on injured tissue and the semisolids containing the nanoencapsulated coenzyme Q10 reduced oxidative parameters assessment through the non-protein thiols levels and lipid peroxidation. This way, the semisolids based on nanocapsules may be considered a promising approach for the treatment and prevention of skin inflammation diseases.
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Nanoestructuras/química , Traumatismos por Radiación/tratamiento farmacológico , Piel/efectos de la radiación , Tocoferoles/química , Ubiquinona/análogos & derivados , Acetilglucosaminidasa/metabolismo , Administración Cutánea , Animales , Edema/tratamiento farmacológico , Edema/patología , Concentración de Iones de Hidrógeno , Inflamación , Leucocitos/citología , Luz , Peroxidación de Lípido , Ratones , Nanocápsulas/química , Estrés Oxidativo , Tamaño de la Partícula , Peroxidasa/química , Polisacáridos/química , Polisacáridos Bacterianos/química , Traumatismos por Radiación/fisiopatología , Reología , Piel/efectos de los fármacos , Compuestos de Sulfhidrilo/química , Quemadura Solar/prevención & control , Ubiquinona/química , Rayos UltravioletaRESUMEN
Peripheral inflammatory stimuli may activate a brain neuroinflammatory processes with consequences in brain function. The present study investigated if anthocyanins (ANT) consumption was able to prevent the memory loss, the neuronal damage, and the neuroinflammatory processes triggered by the intraperitoneal lipopolysaccharide (LPS) administration. C57BL6 male mice were treated with ANT (30-100 mg/kg by gavage). With a single dose or during 10 days, before be challenged with LPS (250 µg/kg intraperitoneally single administration), a classical inductor of inflammation. The data obtained showed that ANT was able to confer protection against the memory impairment after 10 days of ANT treatment (100 mg/kg). This phytonutrient also prevented the hypothermia episode induced by LPS. Moreover, ANT prevented the increase in protein carbonyl, NOx, and MDA levels in the hippocampus and cerebral cortex (4 and 24 h) in animal challenged with LPS. ANT showed a protective effect on the increase in the pro-inflammatory cytokines content, especially Interleukin (IL)-1ß, tumoral necrosis factor-α and on the reduction of IL-10 induced by LPS. ANT 100 mg/kg prevented the infiltration of peripheral immune cells in the hippocampus at 24 h post-LPS administration. In parallel, LPS increased the activity of myeloperoxidase in cortex and hippocampus, and ANT prevented this effect, also reducing microglia (Iba-1) and astrocyte (GFAP) immunoreactivity. Thus, our data support that ANT are a promising therapeutic component against brain disorders associated with process of neuroinflammation. Graphical Abstract á .
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Antocianinas/uso terapéutico , Inflamación/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Animales , Antocianinas/farmacología , Corteza Cerebral/enzimología , Corteza Cerebral/patología , Hipocampo/enzimología , Hipocampo/patología , Hipotermia Inducida , Inflamación/complicaciones , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/administración & dosificación , Masculino , Trastornos de la Memoria/complicaciones , Ratones Endogámicos C57BL , Modelos Biológicos , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Neuroglía/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Peroxidasa/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
The venom of the Brazilian armed spider Phoneutria nigriventer is a rich source of biologically active peptides that have potential as analgesic drugs. In this study, we investigated the analgesic and adverse effects of peptide 3-5 (Tx3-5), purified from P. nigriventer venom, in several mouse models of pain. Tx3-5 was administered by intrathecal injection to mice selected as models of postoperative (plantar incision), neuropathic (partial sciatic nerve ligation) and cancer-related pain (inoculation with melanoma cells) in animals that were either sensitive or tolerant to morphine. Intrathecal administration of Tx3-5 (3-300 fmol/site) in mice could either prevent or reverse postoperative nociception, with a 50 % inhibitory dose (ID50) of 16.6 (3.2-87.2) fmol/site and a maximum inhibition of 87 ± 10 % at a dose of 30 fmol/site. Its effect was prevented by the selective activator of L-type calcium channel Bay-K8644 (10 µg/site). Tx3-5 (30 fmol/site) also produced a partial antinociceptive effect in a neuropathic pain model (inhibition of 67 ± 10 %). Additionally, treatment with Tx3-5 (30 fmol/site) nearly abolished cancer-related nociception with similar efficacy in both morphine-sensitive and morphine-tolerant mice (96 ± 7 and 100 % inhibition, respectively). Notably, Tx3-5 did not produce visible adverse effects at doses that produced antinociception and presented a TD50 of 1125 (893-1418) fmol/site. Finally, Tx3-5 did not alter the normal mechanical or thermal sensitivity of the animals or cause immunogenicity. Our results suggest that Tx3-5 is a strong drug candidate for the treatment of painful conditions.
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Analgésicos/uso terapéutico , Dolor en Cáncer/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Neuropéptidos/uso terapéutico , Neurotoxinas/uso terapéutico , Venenos de Araña/uso terapéutico , Analgésicos/efectos adversos , Analgésicos/farmacología , Animales , Agonistas de los Canales de Calcio/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuropéptidos/efectos adversos , Neuropéptidos/farmacología , Neurotoxinas/efectos adversos , Neurotoxinas/farmacología , Nocicepción/efectos de los fármacos , Venenos de Araña/efectos adversos , Venenos de Araña/farmacologíaRESUMEN
OBJECTIVE: Verify the role of the kinin B1 receptors (B1R) and the effect of ACE inhibitors (ACEi) on acute gout induced by monosodium urate (MSU) crystals in rodents. METHODS: Painful (overt pain and allodynia) and inflammatory parameters (joint oedema, leukocyte trafficking, interleukin-1ß levels) of acute gout attacks were assessed several hours after an intra-articular injection of MSU (1.25 or 0.5 mg/articulation) into the ankle of rats or mice, respectively. The role of B1R was investigated using pharmacological antagonism or gene deletion. Additionally, B1R immunoreactivity in ankle tissue and sensory neurons, kininase I activity and des-Arg(9)-bradykinin synovial levels were also measured. Similar tools were used to investigate the effects of ACEi on a low dose of MSU (0.0125 mg/articulation)-induced inflammation. RESULTS: Kinin B1R antagonism or gene deletion largely reduced all painful and inflammatory signs of gout. Furthermore, MSU increased B1R expression in articular tissues, the content of the B1 agonist des-Arg(9)-bradykinin and the activity of the B1 agonist-forming enzyme kininase I. A low dose of MSU crystals, which did not induce inflammation in control animals, caused signs of acute gout attacks in ACEi-treated animals that were B1R-dependent. CONCLUSIONS: Kinin B1R contributes to acute gouty attacks, including the ones facilitated by ACEi. Therefore, B1R is a potential therapeutic target for the treatment and prophylaxis of gout, especially in patients taking ACEi.
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Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Gota/metabolismo , Receptor de Bradiquinina B1/fisiología , Enfermedad Aguda , Animales , Antagonistas del Receptor de Bradiquinina B1/uso terapéutico , Dioxoles/uso terapéutico , Edema/inducido químicamente , Edema/metabolismo , Gota/inducido químicamente , Gota/tratamiento farmacológico , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Dolor/inducido químicamente , Dolor/metabolismo , Ratas Wistar , Sulfonamidas/uso terapéutico , Ácido ÚricoRESUMEN
This study reports a facile and controllable synthetic method for the preparation of both 1,3- and 1,5-isomers of 4-(3(5)-aryl-3(5)-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamides, as well as a new series of 4-(3-aryl-5-hydroxy-5-(trifluoromethyl)-4,5-dihydropyrazol-1-yl)benzenesulfonamides, from the cyclocondensation reaction of 4-aryl-1,1,1-trifluoro-4-methoxybut-3-en-2-ones or 1-aryl-4,4,4-trifluoro-butane-1,3-diones or their enolic forms with 4-hydrazinylbenzenesulfonamide. All compounds of the new series of 3-substituted 1-(4-benzenesulfonamide)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydropyrazoles were tested for their effect on a pathological pain model in mice. The compounds 3a, 3b, 3c, 3e, and 3f presented anti-hyperalgesic action, while the compounds 3a, 3c, 3d, 3f, and 3g exhibited anti-edematogenic effects, without causing locomotive disorders in animals, thus making them comparable to Celecoxib in an arthritic pain model.
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Hidrocarburos Fluorados/síntesis química , Hiperalgesia/tratamiento farmacológico , Sulfonamidas/síntesis química , Sulfonamidas/uso terapéutico , Animales , Celecoxib , Modelos Animales de Enfermedad , Edema/tratamiento farmacológico , Edema/patología , Hidrocarburos Fluorados/química , Hidrocarburos Fluorados/farmacología , Hiperalgesia/patología , Masculino , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Estereoisomerismo , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
OBJECTIVE: Gout is a common cause of inflammatory arthritis and is provoked by the accumulation of monosodium urate (MSU) crystals. However, the underlying mechanisms of the pain associated with acute attacks of gout are poorly understood. The aim of this study was to evaluate the role of transient receptor potential ankyrin 1 (TRPA-1) and TRPA-1 stimulants, such as H2 O2 , in a rodent model of MSU-induced inflammation. METHODS: MSU or H2 O2 was injected into the hind paws of rodents or applied in cultured sensory neurons, and the intracellular calcium response was measured in vitro. Inflammatory or nociceptive responses in vivo were evaluated using pharmacologic, genetic, or biochemical tools and methods. RESULTS: TRPA-1 antagonism, TRPA-1 gene deletion, or pretreatment of peptidergic TRP-expressing primary sensory neurons with capsaicin markedly decreased MSU-induced nociception and edema. In addition to these neurogenic effects, MSU increased H2 O2 levels in the injected tissue, an effect that was abolished by the H2 O2 -detoxifying enzyme catalase. H2 O2 , but not MSU, directly stimulated sensory neurons through the activation of TRPA-1. The nociceptive responses evoked by MSU or H2 O2 injection were attenuated by the reducing agent dithiothreitol. In addition, MSU injection increased the expression of TRPA-1 and TRP vanilloid channel 1 (TRPV-1) and also enhanced cellular infiltration and interleukin-1ß levels, and these effects were blocked by TRPA-1 antagonism. CONCLUSION: Our results suggest that MSU injection increases tissue H2 O2 , thereby stimulating TRPA-1 on sensory nerve endings to produce inflammation and nociception. TRPV-1, by a previously unknown mechanism, also contributes to these responses.
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Dolor Agudo/metabolismo , Artritis Gotosa/metabolismo , Peróxido de Hidrógeno/metabolismo , Inflamación/metabolismo , Canales Catiónicos TRPC/metabolismo , Ácido Úrico/metabolismo , Acetanilidas/farmacología , Dolor Agudo/inducido químicamente , Dolor Agudo/tratamiento farmacológico , Animales , Artritis Gotosa/inducido químicamente , Artritis Gotosa/tratamiento farmacológico , Modelos Animales de Enfermedad , Peróxido de Hidrógeno/farmacología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Masculino , Ratones , Ratones Noqueados , Oxidantes/metabolismo , Oxidantes/farmacología , Purinas/farmacología , Ratas , Ratas Wistar , Células Receptoras Sensoriales/metabolismo , Canal Catiónico TRPA1 , Canales Catiónicos TRPC/agonistas , Canales Catiónicos TRPC/antagonistas & inhibidores , Ácido Úrico/farmacologíaRESUMEN
Abdominal pain is a frequent symptom of peritoneal cavity irritation, but little is known about the role of the receptors for irritant substances, transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1), in this painful condition. Thus, we investigated the abdominal nociception caused by peritoneal stimulation with TRPV1 (capsaicin) and TRPA1 (allyl isothiocyanate, AITC) agonists and their mechanisms in rats. The intraperitoneal (i.p.) injection of either capsaicin or AITC (0.03-10 mg/kg) induced short-term (up to 20 min) and dose-dependent abdominal nociception, and also produced c-fos expression in spinal afferents of the dorsal horn. TRPV1 antagonism prevented (94 ± 4% inhibition) nociception induced by capsaicin but not by AITC. In contrast, the TRPA1 antagonism almost abolished AITC-induced nociception (95 ± 2% inhibition) without altering the capsaicin response. Moreover, nociception induced by either capsaicin or AITC was reduced by the desensitisation of TRPV1-positive sensory fibres with resiniferatoxin (73 ± 18 and 76 ± 15% inhibitions, respectively) and by the NK1 receptor antagonist aprepitant (56 ± 5 and 53 ± 8% inhibitions, respectively). Likewise, the i.p. injections of capsaicin or AITC increased the content of substance P in the peritoneal fluid. Nevertheless, neither the mast cell membrane stabiliser cromoglycate, nor the H1 antagonist promethazine, nor depletion of peritoneal macrophages affected abdominal nociception induced either by capsaicin or AITC. Accordingly, neither capsaicin nor AITC increased the histamine content in the peritoneal fluid or provoked peritoneal mast cell degranulation in vitro. Collectively, our findings suggest that TRPV1 and TRPA1 stimulation in the peritoneum produces abdominal nociception that is mediated by sensory fibres activation.
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Nocicepción , Peritoneo/efectos de los fármacos , Canales Catiónicos TRPC/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Capsaicina/farmacología , Tránsito Gastrointestinal/efectos de los fármacos , Intestinos/efectos de los fármacos , Intestinos/fisiología , Isotiocianatos/farmacología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Masculino , Mastocitos/citología , Mastocitos/efectos de los fármacos , Nocicepción/efectos de los fármacos , Peritoneo/inmunología , Peritoneo/metabolismo , Peritoneo/fisiología , Ratas , Ratas Wistar , Receptores de Neuroquinina-1/metabolismo , Sustancia P/farmacología , Canal Catiónico TRPA1 , Canales Catiónicos TRPC/agonistas , Canales Catiónicos TRPV/agonistasRESUMEN
Pyrazole compounds are an intriguing class of compounds with potential analgesic activity; however, their mechanism of action remains unknown. Thus, the goal of this study was to explore the antinociceptive potential, safety and mechanism of action of novel 1-pyrazole methyl ester derivatives, which were designed by molecular simplification, using in vivo and in vitro methods in mice. First, tree 1-pyrazole methyl ester derivatives (DMPE, MPFE, and MPCIE) were tested in the capsaicin test and all presented antinociceptive effect; however the MPClE (methyl 5-trichloromethyl-3-methyl-1H-pyrazole-1-carboxylate) was the most effective. Thus, we selected this compound to assess the effects and mechanisms in subsequent pain models. MPCIE produced antinociception when administered by oral, intraperitoneal, intrathecal and intraplantar routes and was effective in the capsaicin and the acetic acid-induced nociception tests. Moreover, this compound reduced the hyperalgesia in diverse clinically-relevant pain models, including postoperative, inflammatory, and neuropathic nociception in mice. The antinociception produced by orally administered MPClE was mediated by κ-opioid receptors, since these effects were prevented by systemically pre-treatment with naloxone and the κ-opioid receptor antagonist nor-binaltorphimine. Moreover, MPCIE prevented binding of the κ-opioid ligand [(3)H]-CI-977 in vitro (IC50 of 0.68 (0.32-1.4) µM), but not the TRPV1 ([(3)H]-resiniferatoxin) or the α2-adrenoreceptor ([(3)H]-idazoxan) binding. Regarding the drug-induced side effects, oral administration of MPClE did not produce sedation, constipation or motor impairment at its active dose. In addition, MPCIE was readily absorbed after oral administration. Taken together, these results demonstrate that MPClE is a novel, potent, orally active and safe analgesic drug that targets κ-opioid receptors.
Asunto(s)
Analgésicos/farmacología , Pirazoles/farmacología , Receptores Opioides kappa/agonistas , Antagonistas de Receptores Adrenérgicos alfa 2 , Analgésicos/administración & dosificación , Analgésicos/antagonistas & inhibidores , Analgésicos/química , Animales , Benzofuranos , Diterpenos , Vías de Administración de Medicamentos , Evaluación Preclínica de Medicamentos , Idazoxan , Masculino , Ratones , Estructura Molecular , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor , Pirazoles/administración & dosificación , Pirazoles/antagonistas & inhibidores , Pirazoles/química , Pirrolidinas , Ensayo de Unión Radioligante , Receptores Opioides kappa/antagonistas & inhibidores , Canales Catiónicos TRPV/efectos de los fármacos , TritioRESUMEN
OBJECTIVE AND DESIGN: We investigated the effect of glibenclamide on inflammatory parameters in a model of acute gouty attack in rats. TREATMENT: Intra-articular injection of 50 µl of monosodium urate (MSU) crystals (1.25 mg/site) was used to induce gout-related inflammation. The effects of glibenclamide (1-10 mg/kg, s.c.) or dexamethasone (8 mg/kg, s.c., positive control) were assessed on several inflammation parameters. METHODS: Spontaneous nociception assessment, edema measurement, total and differential leucocyte counts, interleukin (IL)-1ß release, prostaglandin E2 production and determination of blood glucose levels were analyzed. Peritoneal macrophages were incubated with MSU and levels of IL-1ß were measured. Statistical significance was assessed by one- or two-way analysis of variance. RESULTS: Glibenclamide (3 mg/kg) or dexamethasone (8 mg/kg) prevented nociception and edema induced by MSU injection in rats. Glibenclamide did not affect leukocyte infiltration, IL-1ß release and PGE2 production, but only reduced IL-1ß production by MSU-stimulated macrophages at very high concentration (200 µM). Dexamethasone significantly reduced leukocyte infiltration, IL-1ß release and PGE2 production. Glibenclamide reduced whereas dexamethasone increased blood glucose levels of MSU-injected rats. CONCLUSIONS: Glibenclamide reduced nociception and edema, but not leukocyte infiltration, IL-1ß release and PGE2 production. However, its substantial effect on nociception and edema suggests that glibenclamide can be an interesting option as an adjuvant treatment for pain induced by acute attacks of gout.
Asunto(s)
Analgésicos/uso terapéutico , Antiinflamatorios/uso terapéutico , Gliburida/uso terapéutico , Gota/tratamiento farmacológico , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Dinoprostona/inmunología , Modelos Animales de Enfermedad , Gliburida/farmacología , Gota/inducido químicamente , Gota/inmunología , Interleucina-1beta/inmunología , Recuento de Leucocitos , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/inmunología , Masculino , Ratas , Ratas Wistar , Ácido ÚricoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Lavandula angustifolia (lavender) inhalation has been used in folk medicine for the treatment of anxiety, and clinical and animal studies have corroborated its anxiolytic effect, although its mechanism of action is still not fully understood. AIMS OF THE STUDY: The objective of the present study was to determine whether the GABAA/benzodiazepine complex or serotonin neurotransmission mediates the anxiolytic-like effect of lavender essential oil. MATERIALS AND METHODS: Male Swiss mice were subjected to the marble-burying test after being exposed to the aroma of lavender essential oil (1-5%), amyl acetate (5%; used as a behaviorally neutral odor), or distilled water for 15 min via inhalation. Additionally, the effect of 5% lavender essential oil was also evaluated in mice subjected to the elevated plus maze. GABAA/benzodiazepine mediation was evaluated by pretreating the mice with the GABAA receptor antagonist picrotoxin before the marble burying test and [(3)H]flunitrazepam binding to the benzodiazepine site on the GABAA receptor. Serotonergic mediation was studied by pretreating the mice with O-methyl-[3H]-N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635), a serotonin 5-HT1A receptor antagonist before the marble burying test. We also evaluated changes in the pharmacologically induced serotonin syndrome and the effects of combined administration of subeffective doses of lavender essential oil and the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). RESULTS: Lavender essential oil (1-5%) decreased the number of marbles buried compared with the control and amyl acetate groups. In the elevated plus maze, 5% lavender essential oil inhalation increased the percentage of time spent on and number of entries into the open arms compared with controls. No effect was seen in the number of closed arm entries or number of beam interruptions in the automated activity chamber. Pretreatment with the GABAA receptor antagonist picrotoxin (0.5mg/kg) did not modify the behavioral effect of 5% lavender essential oil in the marble-burying test. Lavender essential oil also did not alter [(3)H]flunitrazepam binding to the benzodiazepine site on the GABAA receptor. Pretreatment with the serotonin 5-HT1A receptor antagonist WAY100635 (3mg/kg) blocked the anxiolytic-like effect of lavender essential oil and the 5-HT1A receptor agonist 8-OH-DPAT (3mg/kg). A combination of ineffective doses of 8-OH-DPAT (0.5mg/kg) and lavender essential oil (0.1%) reduced the number of marbles buried. Finally, 5% lavender essential oil attenuated the serotonin syndrome induced by 40 mg/kg fluoxetine plus 80 mg/kg 5-hydroxytryptophan. CONCLUSIONS: These results indicate an important role for the serotonergic system in the anxiolytic-like effect of lavender essential oil.
Asunto(s)
Ansiolíticos/administración & dosificación , Aceites Volátiles/administración & dosificación , Aceites de Plantas/administración & dosificación , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Administración por Inhalación , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Diazepam/metabolismo , Flunitrazepam/metabolismo , Antagonistas de Receptores de GABA-A/farmacología , Lavandula , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Picrotoxina/farmacología , Piperazinas/farmacología , Piridinas/farmacología , Ratas , Receptores de GABA-A/metabolismo , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Síndrome de la Serotonina , Transmisión SinápticaRESUMEN
BACKGROUND: Studies have indicated that nearly half of all surgical patients still have inadequate pain relief. Thus, it is crucial to understand the mechanisms involved in postoperative pain in order to better treat it. Thus, the aim of this study was to investigate the involvement of mast cell degranulation, tryptase and its substrate, the protease-activated receptor 2, in a model of postoperative pain in mice. METHODS: We evaluated the effect of the compound 48/80 (to cause mast cell mediator depletion), cromoglycate or ketotifen (mast cell stabilizers), gabexate (tryptase inhibitor) or N3-methylbutyryl-N-6-aminohexanoyl-piperazine (protease-activated receptor 2 antagonist) in a postoperative pain model in mice (n = 5-10). Mast cell degranulation and tryptase activity were also evaluated in the operated tissue (n= 5-8). RESULTS: The pre-treatment with compound 48/80 or ketotifen was able to prevent nociception throughout the postoperative hyperalgesia course (until 5 days after surgery), whereas cromoglycate presented a shorter effect (until 1 day). Gabexate or N3-methylbutyryl-N-6-aminohexanoyl-piperazine also produced a short-lasting effect in preventing postoperative nociception. However, neither gabexate, N3-methylbutyryl-N-6-aminohexanoyl-piperazine nor cromoglycate was capable of reversing nociception when administered after incision. Surgery led to early mast cell degranulation on the incised tissue and increased tryptase activity in tissue perfusates. Cromoglycate fully prevented the tryptase release in the perfusate and the compound 48/80 substantially reduced tryptase activity in the incised tissue. CONCLUSION: Thus, the mast cell degranulation with the subsequent release of tryptase and protease-activated receptor 2 activation are potential targets for the development of novel therapies to prevent, but not reverse, postoperative pain.
Asunto(s)
Mastocitos/metabolismo , Dolor Postoperatorio/etiología , Dolor Postoperatorio/metabolismo , Receptor PAR-2/metabolismo , Triptasas/fisiología , Animales , Degranulación de la Célula/fisiología , Terapia de Inmunosupresión/métodos , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/enzimología , Ratones , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Dolor Postoperatorio/prevención & control , Piperazinas/farmacología , Piperazinas/uso terapéutico , Receptor PAR-2/antagonistas & inhibidores , Receptor PAR-2/fisiología , Triptasas/antagonistas & inhibidoresRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Jatropha isabellei Müll Arg. (Euphorbiaceae) is a medicinal plant that has been used in South American folk medicine for the treatment of arthritic diseases, particularly gout. AIM OF THE STUDY: This study was designed to verify the antinociceptive, anti-inflammatory and hypouricemic potential of Jatropha isabellei. MATERIALS AND METHODS: Rats were orally administered with the crude extract (100-300 mg/kg) or a fraction that is rich in alkaloids (0.15 mg/kg) of Jatropha isabellei. An intra-articular (i.a.) injection of 50 µl of monosodium urate (MSU) crystals (1.25mg/site) was used to generate the gout model to assess the effect of the treatment on nociception (thermal and mechanical hyperalgesia) and inflammation (oedema and neutrophil infiltration). The effect of Jatropha isabellei on the serum levels of uric acid was evaluated in a model of hyperuricaemia induced by the intraperitoneal injection of potassium oxonate (250 mg/kg). The side effects were analysed using an open-field test, gastric lesion assessment and by measuring the levels of the ALT and AST enzymes. RESULTS: Our study demonstrated that the crude extract of Jatropha isabellei and a fraction rich in alkaloids were able to prevent the thermal hyperalgesia, mechanical allodynia, oedema and neutrophil infiltration induced by intra-articular MSU injection in rats. On the other hand, treatment with Jatropha isabellei did not alter the uric acid levels increased by potassium oxonate in the hyperuricaemia model. In addition, Jatropha isabellei did not induce gastric lesions or liver damage and did not alter spontaneous locomotor activity. CONCLUSION: The crude extract of Jatropha isabellei and its fraction rich in alkaloid presents antinociceptive and anti-inflammatory effects in a rat gout model, similar to that observed after treatment with colchicine, supporting the traditional use of this plant in gouty patients.
Asunto(s)
Antiinflamatorios/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Jatropha/química , Fitoterapia/métodos , Extractos Vegetales/uso terapéutico , Alcaloides/química , Alcaloides/aislamiento & purificación , Alcaloides/uso terapéutico , Animales , Antiinflamatorios/efectos adversos , Antiinflamatorios/química , Antiinflamatorios/farmacología , Artritis Gotosa/inducido químicamente , Artritis Gotosa/tratamiento farmacológico , Biomarcadores Farmacológicos/metabolismo , Modelos Animales de Enfermedad , Edema/tratamiento farmacológico , Hiperuricemia/sangre , Hiperuricemia/inducido químicamente , Hiperuricemia/tratamiento farmacológico , Masculino , Actividad Motora/efectos de los fármacos , Infiltración Neutrófila/efectos de los fármacos , Ácido Oxónico , Peroxidasa/metabolismo , Extractos Vegetales/efectos adversos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/metabolismo , Ácido Úrico/metabolismo , Xantina Oxidasa/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Geissospermum vellosii is a tree widely found throughout the Amazonic forest and frequently used by the native population for painful disorders. AIM OF THE STUDY: The present study examined the antinociceptive effects of Geissospermum vellosii in behavioral models of nociception. MATERIALS, METHODS AND RESULTS: Oral administration of crude extract of Geissospermum vellosii or its dichloromethane fraction (1-100 mg/kg) inhibited formalin-induced inflammatory nociception and acetic acid-induced visceral nociception. The antinociceptive effect of Geissospermum vellosii was unrelated with motor dysfunctions. Furthermore, the alkaloid 12-metoxy-1-methyl-aspidospermidine (0.001-1 mg/kg), isolated from the dichloromethane fraction, also produced antinociception. The antinociception caused by the dichloromethane fraction was significantly attenuated by pre-treatment of mice with p-chlorophenylalanine methyl ester (PCPA, an inhibitor of serotonin synthesis, 100 mg/kg once a day for 4 consecutive days) and WAY-100635 (a 5-HT(1A) receptor antagonist, 0.3 mg/kg). In contrast, dichloromethane fraction antinociception was not affected by pre-treatment of animals with ketanserin (a 5-HT(2) receptor antagonist, 0.3 mg/kg) or ondansetron (a 5-HT(3) receptor antagonist, 0.5 mg/kg). CONCLUSIONS: Together, these results indicate that Geissospermum vellosii produces antinociception through an interaction with 5-HT(1A) receptors. Furthermore, the alkaloid 12-metoxy-1-methyl-aspidospermidine contributes to the antinociceptive properties reported for Geissospermum vellosii.
Asunto(s)
Analgésicos/farmacología , Apocynaceae/química , Extractos Vegetales/farmacología , Receptor de Serotonina 5-HT1A/fisiología , Ácido Acético/administración & dosificación , Animales , Formaldehído/administración & dosificación , Locomoción/efectos de los fármacos , Masculino , RatonesRESUMEN
Pain is the most common complaint in the medical field and the identification of compounds that can effectively treat painful states without induction of side-effects remains a major challenge in biomedical research. The aim of the present study was to investigate the antinociceptive effect of a novel compound, 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole (compound A) in several models of pain in mice and compare with those produced by the known trifluoromethyl-containing pyrazole compound celecoxib. Compound A or celecoxib were administrated by oral (78-780 micromol/kg), intrathecal (9-22.5 nmol/site) or intracerebroventricular (9-22.5 nmol/site) routes. Oral administration of either compound A or celecoxib abolished the mechanical allodynia, but not the oedema caused by intraplantar injection of carrageenan. Similarly, compound A reduced the overt nociception, but not the oedema, produced by bradykinin or capsaicin. However, compound A (500 micromol/kg, orally) did not alter nociception nor oedema caused by intraplantar injection of prostaglandin E(2 )or glutamate, whereas celecoxib reduced only the nociception induced by the former. Moreover, oral and intrathecal administration of compound A or celecoxib also reduced the nociception induced by acetic acid. However, only celecoxib reduced the acetic acid-induced nociception when it was injected by the intracerebroventricular route. Finally, neither compound A nor celecoxib was able to produce antinociceptive effect in the tail-flick test or to alter the motor performance and the body temperature. Besides, compound A or celecoxib did not induce gastric lesion. Thus, compound A seems to be an interesting prototype for the development of novel analgesic drugs.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Dolor/tratamiento farmacológico , Pirazoles/uso terapéutico , Compuestos de Tosilo/uso terapéutico , Administración Oral , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Temperatura Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Edema/tratamiento farmacológico , Femenino , Inyecciones Intraventriculares , Inyecciones Espinales , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Dimensión del Dolor , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Estómago/efectos de los fármacos , Estómago/patología , Factores de Tiempo , Compuestos de Tosilo/administración & dosificación , Compuestos de Tosilo/efectos adversosRESUMEN
AIMS: The aim of the present study was to evaluate the antinociceptive effect of the novel pyrazoline methyl ester: 4-methyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole methyl ester (MPF4). MAIN METHODS: The effect of MPF4 was assessed in two models of pain: arthritic pain caused by Complete Freund's Adjuvant (CFA) and postoperative pain caused by surgical incision in mice. KEY FINDINGS: MPF4 given intraperitoneally (1.0 mmol/kg, i.p.) produced marked antinociception in inflammatory allodynia caused by CFA. The antinociceptive effect produced by MPF4 was reversed with the pre-treatment of animals with naloxone or naltrindole. Oral administration of MPF4 (1.0 mmol/kg, p.o), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.) also produced an anti-allodynic effect. However, none of the compounds evaluated reversed the paw edema produced by CFA. Moreover, MPF4, dipyrone and morphine also produced an anti-allodynic effect in the surgical incisional pain model. The maximal inhibitions obtained with preemptive drug treatment were 66+/-7%, 73+/-9% and 88+/-8% for MPF4 (1.0 mmol/kg, p.o.), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.), respectively. The maximal inhibitions obtained with curative drug treatment were 53+/-9%, 83+/-7% and 84+/-7%, for MPF4, dipyrone and morphine, respectively. Unlike indomethacin, MPF4 did not induce gastric lesions at the dose that caused the highest antinociception (1.0 mmol/kg, p.o). The anti-allodynic action of MPF4, dipyrone and morphine was not associated with impairment of motor activity. SIGNIFICANCE: The results of the present study suggest that MPF4 represents a potential target for the development of new drugs to treat persistent inflammatory pain.
Asunto(s)
Analgésicos/farmacología , Inflamación/complicaciones , Dolor/tratamiento farmacológico , Dolor/etiología , Pirazoles/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/complicaciones , Dipirona/farmacología , Dipirona/uso terapéutico , Adyuvante de Freund , Indometacina/farmacología , Indometacina/uso terapéutico , Inflamación/inducido químicamente , Masculino , Ratones , Morfina/farmacología , Morfina/uso terapéutico , Actividad Motora/efectos de los fármacos , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/psicología , Equilibrio Postural/efectos de los fármacos , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/patologíaRESUMEN
The aim of the present study was to evaluate the antinociceptive potential of four novel pyrazoline methyl ester compounds on chemical and thermal models of pain in mice. The following 5-trihalomethylated-4,5-dihydro-1H-pyrazole methyl ester compounds were tested: 3-methyl-5-trifluoromethyl-(MPF3), 4-methyl-5-trifluoromethyl-(MPF4), 3-methyl-5-trichloromethyl-(MPCl3) and 4-methyl-5-trichloromethyl-(MPCl4). MPF3, MPF4, MPCl3 and MPCl4 (0.03-1.0 mmol/kg) given intraperitoneally decreased neurogenic and inflammatory phases of nociception in the formalin test. Moreover, MPF3, MPF4, MPCl3, MPCl4 (0.1-1.0 mmol/kg) and dipyrone (1.5 mmol/kg) also produced a dose-dependent antinociceptive effect in the hot-plate test. However, MPF3, MPF4, MPCl3 and MPCl4 did not impair motor coordination in the rotarod test or spontaneous locomotion in the open field test. The antinociceptive effect of MPF4 (1.0 mmol/kg, i.p.) was reversed by the opioid receptor antagonist naloxone (2 mg/kg, i.p.), but not by the alpha(2)-adrenergic receptor antagonist yohimbine (0.15 mg/kg, i.p.) or by p-chlorophenylalanine ethyl ester (PCPA, 300 mg/kg, i.p.) treatment. In contrast to morphine (5 mg/kg, i.p.), MPF4 given daily for up to 8 days did not generate a tolerance to its antinociceptive effect. However, similar to morphine (11 mg/kg, i.p.), MPF4 reduced gastrointestinal transit in mice. Taken together these results demonstrate that these novel pyrazoline methyl esters tested may be promising prototypes of additional mild analgesics.