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BACKGROUND: The Nociception Level Index has shown benefits in estimating the nociception/antinociception balance in adults, but there is limited evidence in the pediatric population. Evaluating the index performance in children might provide valuable insights to guide opioid administration. AIMS: To evaluate the Nociception Level Index ability to identify a standardized nociceptive stimulus and the analgesic effect of a fentanyl bolus. Additionally, to characterize the pharmacokinetic/pharmacodynamic relationship of fentanyl with the Nociception Level Index response during sevoflurane anesthesia. METHODS: Nineteen children, 5.3 (4.1-6.7) years, scheduled for lower abdominal or urological surgery, were studied. After sevoflurane anesthesia and caudal block, a tetanic stimulus (50 Hz, 60 mA, 5 s) was performed in the forearm. Following the administration of fentanyl 2 µg/kg intravenous bolus, three similar consecutive tetanic stimuli were performed at 5-, 15-, and 30-min post-fentanyl administration. Changes in the Nociception Level Index, heart rate, mean arterial pressure, and bispectral index were compared in response to the tetanic stimuli. Fentanyl plasma concentrations and the Nociception Level Index data were used to elaborate a pharmacokinetic/pharmacodynamic model using a sequential modeling approach in NONMEM®. RESULTS: After the first tetanic stimulus, both the Nociception Level Index and the heart rate increased compared to baseline (8 ± 7 vs. 19 ± 10; mean difference (CI95) -12(-18--6) and 100 ± 10 vs. 102 ± 10; -2(-4--0.1)) and decrease following fentanyl administration (19 ± 10 vs. 8 ± 8; 12 (5-18) and 102 ± 10 vs. 91 ± 11; 11 (7-16)). In subsequent tetanic stimuli, heart rate remained unchanged, while the Nociception Level Index progressively increased within 15 min to values similar to those before fentanyl. An allometric weight-scaled, 3-compartment model best characterized the pharmacokinetic profile of fentanyl. The pharmacokinetic/pharmacodynamic modeling analysis revealed hysteresis between fentanyl plasma concentrations and the Nociception Level Index response, characterized by plasma effect-site equilibration half-time of 1.69 (0.4-2.9) min. The estimated fentanyl C50 was 1.93 (0.73-4.2) ng/mL. CONCLUSION: The Nociception Level Index showed superior capability compared to traditional hemodynamic variables in discriminating different nociception-antinociception levels during varying fentanyl concentrations in children under sevoflurane anesthesia.
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Analgésicos Opioides , Anestesia General , Anestésicos por Inhalación , Fentanilo , Nocicepción , Sevoflurano , Humanos , Fentanilo/farmacocinética , Fentanilo/administración & dosificación , Fentanilo/farmacología , Sevoflurano/farmacología , Sevoflurano/farmacocinética , Sevoflurano/administración & dosificación , Masculino , Femenino , Niño , Nocicepción/efectos de los fármacos , Preescolar , Anestésicos por Inhalación/farmacocinética , Anestésicos por Inhalación/farmacología , Anestésicos por Inhalación/administración & dosificación , Anestesia General/métodos , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Anestésicos Intravenosos/farmacocinética , Anestésicos Intravenosos/farmacología , Anestésicos Intravenosos/administración & dosificación , Éteres Metílicos/farmacocinética , Éteres Metílicos/farmacología , Éteres Metílicos/administración & dosificaciónRESUMEN
OBJECTIVES: Investigate whether and which synoviocytes would acquire trained immunity characteristics that could exacerbate joint inflammation following a secondary Staphylococcus aureus infection. METHODS: Lipopolysaccharide (LPS) and S. aureus were separately or double injected (21 days of interval) into the tibiofemoral joint cavity of male C57BL/6 mice. At different time points after these stimulations, mechanical nociception was analyzed followed by the analysis of signs of inflammation and damage in the affected joints. The trained immunity markers, including the glycolytic and mTOR pathway, were analyzed in whole tissue or isolated synoviocytes. A group of mice was treated with Rapamycin, an mTOR inhibitor before LPS or S. aureus stimulation. RESULTS: The double LPS - S. aureus hit promoted intense joint inflammation and damage compared to single joint stimulation, including markers in synoviocyte activation, production of proinflammatory cytokines, persistent nociception, and bone damage, despite not reducing the bacterial clearance. The double LPS - S. aureus hit joints increased the synovial macrophage population expressing CX3CR1 alongside triggering established epigenetic modifications associated with trained immunity events in these cells, such as the upregulation of the mTOR signaling pathway (p-mTOR and HIF1α) and the trimethylation of histone H3. Mice treated with Rapamycin presented reduced CX3CR1+ macrophage activation, joint inflammation, and bone damage. CONCLUSIONS: There is a trained immunity phenotype in CX3CR1+ synovial macrophages that contributes to the exacerbation of joint inflammation and damage during septic arthritis caused by S. aureus.
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Lipopolisacáridos , Macrófagos , Ratones Endogámicos C57BL , Infecciones Estafilocócicas , Staphylococcus aureus , Serina-Treonina Quinasas TOR , Animales , Masculino , Infecciones Estafilocócicas/inmunología , Macrófagos/inmunología , Serina-Treonina Quinasas TOR/inmunología , Staphylococcus aureus/inmunología , Receptor 1 de Quimiocinas CX3C/metabolismo , Membrana Sinovial/inmunología , Membrana Sinovial/patología , Artritis Infecciosa/inmunología , Artritis Infecciosa/microbiología , Ratones , Citocinas/inmunología , Citocinas/metabolismo , Sirolimus/farmacología , Inflamación/inmunología , Sinoviocitos/inmunología , Sinoviocitos/efectos de los fármacos , Nocicepción/efectos de los fármacos , Inmunidad EntrenadaRESUMEN
This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.
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Monoterpenos Acíclicos , Analgésicos , Capsaicina , Codeína , Dolor Facial , Dimensión del Dolor , Terpenos , Animales , Codeína/farmacología , Dolor Facial/inducido químicamente , Dolor Facial/tratamiento farmacológico , Monoterpenos Acíclicos/farmacología , Masculino , Dimensión del Dolor/efectos de los fármacos , Capsaicina/farmacología , Terpenos/farmacología , Analgésicos/farmacología , Ratones , Factores de Tiempo , Modelos Animales de Enfermedad , Reproducibilidad de los Resultados , Formaldehído , Ácido Glutámico , Resultado del Tratamiento , Nocicepción/efectos de los fármacos , Análisis de Varianza , Estadísticas no Paramétricas , Conducta Animal/efectos de los fármacosRESUMEN
Noradrenaline (NA) and serotonin (5-HT) induce nociception and antinociception. This antagonistic effect can be explained by the dose and type of activated receptors. We investigated the existence of synergism between the noradrenergic and serotonergic systems during peripheral antinociception. The paw pressure test was performed in mice that had increased sensitivity by intraplantar injection of prostaglandin E2 (PGE2). Noradrenaline (80 ng) administered intraplantarly induced an antinociceptive effect, that was reversed by the administration of selective antagonists of serotoninergic receptors 5-HT1B isamoltan, 5-HT1D BRL15572, 5-HT2A ketanserin, 5-HT3 ondansetron, but not by selective receptor antagonist 5-HT7 SB-269970. The administration of escitalopram, a serotonin reuptake inhibitor, potentiated the antinociceptive effect at a submaximal dose of NA. These results, indicate the existence of synergism between the noradrenergic and serotonergic systems in peripheral antinociception in mice.
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Norepinefrina , Receptores de Serotonina , Antagonistas de la Serotonina , Serotonina , Animales , Ratones , Norepinefrina/metabolismo , Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Masculino , Receptores de Serotonina/metabolismo , Dinoprostona/metabolismo , Citalopram/farmacología , Nocicepción/efectos de los fármacos , Analgésicos/farmacología , Ondansetrón/farmacología , Ketanserina/farmacología , Dolor/tratamiento farmacológico , Dolor/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Burns are a global health problem and can be caused by several factors, including ultraviolet (UV) radiation. Exposure to UVB radiation can cause sunburn and a consequent inflammatory response characterised by pain, oedema, inflammatory cell infiltration, and erythema. Pharmacological treatments available to treat burns and the pain caused by them include nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antimicrobials and glucocorticoids, which are associated with adverse effects. Therefore, the search for new therapeutic alternatives is needed. Diosmetin, an aglycone of the flavonoid diosmin, has antinociceptive, antioxidant and anti-inflammatory properties. Thus, we evaluated the antinociceptive and anti-inflammatory effects of topical diosmetin (0.01, 0.1 and 1%) in a UVB radiation-induced sunburn model in mice. The right hind paw of the anaesthetised mice was exposed only once to UVB radiation (0.75 J/cm2) and immediately treated with diosmetin once a day for 5 days. The diosmetin antinociceptive effect was evaluated by mechanical allodynia and pain affective-motivational behaviour, while its anti-inflammatory activity was assessed by measuring paw oedema and polymorphonuclear cell infiltration. Mice exposed to UVB radiation presented mechanical allodynia, increased pain affective-motivational behaviour, paw oedema and polymorphonuclear cell infiltration into the paw tissue. Topical Pemulen® TR2 1% diosmetin reduced the mechanical allodynia, the pain affective-motivational behaviour, the paw oedema and the number of polymorphonuclear cells in the mice's paw tissue similar to that presented by Pemulen® TR2 0.1% dexamethasone. These findings indicate that diosmetin has therapeutic potential and may be a promising strategy for treating patients experiencing inflammatory pain, especially those associated with sunburn.
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Antiinflamatorios , Modelos Animales de Enfermedad , Flavonoides , Inflamación , Nocicepción , Quemadura Solar , Rayos Ultravioleta , Animales , Quemadura Solar/tratamiento farmacológico , Quemadura Solar/patología , Ratones , Rayos Ultravioleta/efectos adversos , Inflamación/tratamiento farmacológico , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Flavonoides/farmacología , Flavonoides/administración & dosificación , Nocicepción/efectos de los fármacos , Administración Tópica , Analgésicos/farmacología , Analgésicos/administración & dosificación , Edema/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológicoRESUMEN
BACKGROUND: More than 80% of patients may experience acute pain after a surgical procedure, and this is often refractory to pharmacological intervention. The identification of new targets to treat postoperative pain is necessary. There is an association of polymorphisms in the Cav2.3 gene with postoperative pain and opioid consumption. Our study aimed to identify Cav2.3 as a potential target to treat postoperative pain and to reduce opioid-related side effects. EXPERIMENTAL APPROACH: A plantar incision model was established in adult male and female C57BL/6 mice. Cav2.3 expression was detected by qPCR and suppressed by siRNA treatment. The antinociceptive efficacy and safety of a Cav2.3 blocker-alone or together with morphine-was also assessed after surgery. KEY RESULTS: Paw incision in female and male mice caused acute nociception and increased Cav2.3 mRNA expression in the spinal cord but not in the incised tissue. Intrathecal treatment with siRNA against Cav2.3, but not with a scrambled siRNA, prevented the development of surgery-induced nociception in both male and female mice, with female mice experiencing long-lasting effects. High doses of i.t. SNX-482, a Cav2.3 channel blocker, or morphine injected alone, reversed postoperative nociception but also induced side effects. A combination of lower doses of morphine and SNX-482 mediated a long-lasting reversal of postsurgical pain in female and male mice. CONCLUSION: Our results demonstrate that Cav2.3 has a pronociceptive role in the induction of postoperative pain, indicating that it is a potential target for the development of therapeutic approaches for the treatment of postoperative pain.
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Canales de Calcio Tipo R , Dolor Postoperatorio , Médula Espinal , Animales , Femenino , Masculino , Ratones , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/administración & dosificación , Canales de Calcio Tipo R/metabolismo , Canales de Calcio Tipo R/genética , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Morfina/farmacología , Morfina/administración & dosificación , Nocicepción/efectos de los fármacos , Dolor Postoperatorio/metabolismo , Dolor Postoperatorio/tratamiento farmacológico , ARN Interferente Pequeño , Médula Espinal/metabolismo , Médula Espinal/efectos de los fármacosRESUMEN
Caffeine and anabolic-androgenic steroids (AAS) are commonly used to improve muscle mass and athletic performance. Nandrolone Decanoate (ND) is one of the most abused AAS worldwide, leading to behavioral changes in both humans and rodents. Caffeine, the most widely consumed psychostimulant globally, is present in various thermogenic and gym supplements. Low and moderate doses of caffeine antagonize adenosine receptors and have been linked to improved memory and pain relief. We have previously demonstrated that consuming caffeine prevents the risk-taking behavior triggered by nandrolone. In this study, we aimed to investigate the long-term effects of ND and caffeine, either alone or in combination, on passive avoidance memory and nociception. We used the step-down and hot-plate tasks in male and female Lister Hooded rats. Our results confirmed the antinociceptive effect of caffeine and indicated that chronic administration of the ND-caffeine association promotes the evocation of aversive memory in female rats.
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Reacción de Prevención , Cafeína , Memoria , Nandrolona Decanoato , Nocicepción , Animales , Cafeína/farmacología , Femenino , Masculino , Ratas , Nocicepción/efectos de los fármacos , Nandrolona Decanoato/farmacología , Memoria/efectos de los fármacos , Reacción de Prevención/efectos de los fármacos , Nandrolona/farmacología , Nandrolona/análogos & derivados , Estimulantes del Sistema Nervioso Central/farmacología , Anabolizantes/farmacologíaRESUMEN
Abstract: The aim of this study was to evaluate the functional interaction of Glycyrrhiza glabra root extract (GGRE) on the large conductance Ca 2+ - activated K + (BKCa) channels expressed in the peripheral nervo us system by using nociception and inflammation models in rodents in vivo . Besides toxicity studies and open field tests, nociception and inflammation tests were performed on rodents. Different doses of GGRE were given orally to rats and mice. Naloxone, in domethacin, morphine, NS1619 and iberiotoxin (IbTX) were administered. GGRE had both anti - nociceptive and anti - inflammatory activity in rats and mice. GGRE exhibited an analgesic effect by decreasing the time - course of the pain threshold or reaction time i n some nociceptive tests. Furthermore, GGRE reduced level of pro - inflammatory cytokines, including TNF - α and IL - 1ß. As a conclusion, GGRE can alleviate the pain sensation of the afferent nerves and can reduce inflammation and associated pain by activating B KCa channels and reducing the levels of TNF - α, IL1ß
Resumen: El objetivo de este estudio fue evaluar la interacción funcional del extracto de raíz de Glycyrr hiza glabra (GGRE) en los canales de K + (BKCa) activados por Ca 2+ de gran conductancia expresados en el sistema nervioso periférico mediante el uso de modelos de nocicepción e inflamación en roedores in vivo . Además de los estudios de toxicidad y las prueb as de campo abierto, se realizaron pruebas de nocicepción e inflamación en roedores. Se administraron por vía oral diferentes dosis de GGRE a ratas y ratones. Se administraron naloxona, indometacina, morfina, NS1619 e iberiotoxina (IbTX). GGRE tenía activi dad tanto antinociceptiva como antiinflamatoria en ratas y ratones. GGRE mostró un efecto analgésico al disminuir la evolución temporal del umbral del dolor o el tiempo de reacción en algunas pruebas nociceptivas. Además, GGRE redujo el nivel de citocinas proinflamatorias, incluidas TNF - α e IL - 1ß. Como conclusión, GGRE puede aliviar la sensación de dolor de los nervios aferentes y puede reducir la inflamación y el dolor asociado activando los canales BKCa y reduciendo los niveles de TNF - α, IL1ß.
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Animales , Ratas , Extractos Vegetales/administración & dosificación , Glycyrrhiza/química , Neuralgia/tratamiento farmacológico , Fenoles/análisis , Extractos Vegetales/farmacología , Extractos Vegetales/química , Análisis de Varianza , Ratas Wistar , Raíces de Plantas , Modelos Animales , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/efectos de los fármacos , Nocicepción/efectos de los fármacos , InflamaciónRESUMEN
Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2 mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56 days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10 mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5 mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3 mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.
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Endocannabinoides/metabolismo , Nocicepción/efectos de los fármacos , Oxaliplatino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Receptor Cannabinoide CB1/agonistas , Animales , Técnica del Anticuerpo Fluorescente , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/patología , Ganglios Espinales/fisiopatología , Masculino , Ratones , Oxaliplatino/antagonistas & inhibidores , Dimensión del Dolor , Enfermedades del Sistema Nervioso Periférico/metabolismo , Receptor Cannabinoide CB1/metabolismo , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
The musculoskeletal orofacial pain is a complex symptom of Parkinson's disease (PD) resulting in stomatognathic system dysfunctions aggravated by the disease rigidity and postural instability. We tested the effect of cannabidiol (CBD), a non-psychotomimetic constituent of Cannabis sativa, in PD-related myofascial pain. Wistar adult female and male rats orofacial allodynic and hyperalgesic responses were tested by Von Frey and formalin tests, before and 21 days past 6-OHDA lesion. Algesic response was tested after masseter muscle injection of CBD (10, 50, 100 µg in 10 µL) or vehicle. Males compared to females in all estrous cycles' phases presented reduced orofacial allodynia and hyperalgesia. According to the estrous cycle's phases, females presented distinct orofacial nociceptive responses, being the estrus phase well-chosen for nociceptive analysis after 6-OHDA lesion (phase with fewer hormone alterations and adequate length). Dopaminergic neuron lesion decreased mechanical and inflammatory nociceptive thresholds in females and males in a higher proportion in females. CBD local treatment reduced the increased orofacial allodynia and hyperalgesia, in males and females. The female rats were more sensitive to CBD effect considering allodynia, responding to the lowest dose. Although females and males respond to the effect of three doses of CBD in the formalin test, males showed a superior reduction in the hyperalgesic response. These results indicate that hemiparkinsonian female in the estrus phase and male answer differently to the different doses of CBD therapy and nociceptive tests. CBD therapy is effective for parkinsonism-induced orofacial nociception.
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Anticonvulsivantes/farmacología , Cannabidiol/farmacología , Dolor Facial/fisiopatología , Hiperalgesia/fisiopatología , Nocicepción/efectos de los fármacos , Trastornos Parkinsonianos/fisiopatología , Analgésicos/farmacología , Animales , Ciclo Estral/efectos de los fármacos , Ciclo Estral/fisiología , Femenino , Masculino , Oxidopamina/toxicidad , Ratas , Ratas WistarRESUMEN
Peripheral tramadol's delivery in the temporomandibular joint (TMJ) leads to significant analgesic outcomes and inflammatory process's resolvent actions. Mechanistically, these properties are apart from the opioid system. Nevertheless, the molecular mechanisms behind these effects are still unclear. Therefore, the present study investigated the hypothesis that adenosine A1 receptors are involved in the tramadol-induced analgesic and anti-inflammatory effects in the TMJ. Animals were pretreated with an intra-TMJ injection of DPCPX (antagonist of A1 receptor) or tramadol and subsequent nociceptive challenge with an intra-TMJ injection of 1.5% formalin. For over 45 min, the nociceptive behavior was quantitated, and by the end of this assessment, the animals were euthanized, and the periarticular tissue was collected. Lastly, an in vitro assay of BMDM (Bone Marrow-Derived Macrophages) was performed to investigate tramadol activity in macrophages. The intra-TMJ injection of tramadol ameliorates formalin-induced hypernociception along with inhibiting leukocyte migration. The tramadol's peripheral anti-inflammatory effect was mediated by the adenosine A1 receptor and was associated with increased protein expression of α2a-adrenoceptor in the periarticular tissues (p < 0.05: ANOVA, Tukey's test). Also, tramadol inhibits formalin-induced leukocyte migration and protein expression of P2X7 receptors in the periarticular tissue (p < 0.05); however, DPCPX did not alter this effect (p > 0.05). Moreover, DPCPX significantly reduced the protein expression of the M2 macrophage marker, MRC1. In BMDM, tramadol significantly reduces inflammatory cytokines release, and DPCPX abrogated this effect (p < 0.05). We identify tramadol's peripheral effect is mediated by adenosine A1 receptor, possibly expressed in macrophages in the TMJ tissue. We also determined an important discovery related to the activation of A1R/α2a receptors in the tramadol action.
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Agonistas del Receptor de Adenosina A1/administración & dosificación , Artralgia/tratamiento farmacológico , Receptor de Adenosina A1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Tramadol/administración & dosificación , Analgésicos Opioides/administración & dosificación , Animales , Antiinflamatorios/administración & dosificación , Artralgia/inducido químicamente , Artralgia/inmunología , Artralgia/patología , Modelos Animales de Enfermedad , Formaldehído/administración & dosificación , Formaldehído/toxicidad , Humanos , Inyecciones Intraarticulares , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Nocicepción/efectos de los fármacos , Ratas , Articulación Temporomandibular/efectos de los fármacos , Articulación Temporomandibular/inmunología , Articulación Temporomandibular/patología , Xantinas/administración & dosificación , Xantinas/toxicidadRESUMEN
The role of peripheral adenosine receptors in pain is a controversial issue and seems to be quite different from the roles of spinal and central adenosine receptors. The present study is aimed at clarifying the role of these receptors in peripheral nociception. To clarify this, studies were done on Swiss mice with adenosine receptor agonists and antagonists. Nociceptive behavior was induced by subcutaneous injection of glutamate (10 µmol) into the ventral surface of the hind paw of mice. Statistical analyses were performed by one-way ANOVA followed by the Student-Newman-Keuls post hoc test. Results showed that intraplantar (i.pl.) administration of N6-cyclohexyl-adenosine (CHA), an adenosine A1 receptor agonist, at 1 or 10 µg/paw significantly reduced glutamate-induced nociception (p<0.01 and p<0.001 vs. vehicle, respectively, n=8-10). In contrast, i.pl. injection of hydrochloride hydrate (CGS21680, an adenosine A2A receptor agonist) (1 µg/paw) induced a significant increase in glutamate-induced nociception compared to the vehicle (p<0.05, n=8), while 4-(-2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a} {1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, an adenosine A2A receptor antagonist) (20 µg/paw) caused a significant reduction (p<0.05, n=7-8). There were no significant effects on i.pl. administration of four additional adenosine receptor drugs-8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an A1 antagonist, 1-10 µg/paw), N(6)-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA, an A2B agonist, 1-100 µg/paw), alloxazine (an A2B antagonist, 0.1-3 µg/paw), and 2-hexyn-1-yl-N(6)-methyladenosine (HEMADO) (an A3 agonist, 1-100 µg/paw) (p>0.05 vs. vehicle for all tests). We also found that prior administration of DPCPX (3 µg/paw) significantly blocked the anti-nociceptive effect of CHA (1 µg/paw) (p<0.05, n=7-9). Similarly, ZM241385 (20 µg/paw) administered prior to CGS21680 (1 µg/paw) significantly blocked CGS21680-induced exacerbation of nociception (p<0.05, n=8). Finally, inosine (10 and 100 µg/paw), a novel endogenous adenosine A1 receptor agonist recently reported by our research group, was also able to reduce glutamate-induced nociception (p<0.001 vs. vehicle, n=7-8). Interestingly, as an A1 adenosine receptor agonist, the inosine effect was significantly blocked by the A1 antagonist DPCPX (3 µg/paw) (p<0.05, n=7-9) but not by the A2A antagonist ZM241385 (10 µg/paw, p>0.05). In summary, these results demonstrate for the first time that i.pl administration of inosine induces an anti-nociceptive effect, similar to that elicited by CHA and possibly mediated by peripheral adenosine A1 receptor activation. Moreover, our results suggest that peripheral adenosine A2A receptor activation presents a pro-nociceptive effect, exacerbating glutamate-induced nociception independent of inosine-induced anti-nociceptive effects.
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Glutamatos , Nocicepción/efectos de los fármacos , Dolor/inducido químicamente , Dolor/psicología , Sistema Nervioso Periférico/efectos de los fármacos , Receptores Purinérgicos P1/efectos de los fármacos , Agonistas del Receptor de Adenosina A1/farmacología , Antagonistas del Receptor de Adenosina A1/farmacología , Agonistas del Receptor de Adenosina A2/farmacología , Antagonistas del Receptor de Adenosina A2/farmacología , Animales , Femenino , Pie , Glutamatos/administración & dosificación , Inyecciones , Inosina/farmacología , Masculino , Ratones , Dimensión del Dolor/efectos de los fármacos , Receptor de Adenosina A2A/efectos de los fármacosRESUMEN
The aim of this study was to examine if the peripheral antinociception of α-bisabolol involves the participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous injection into the dorsal surface of the paw of vehicles or increasing doses of α-bisabolol (100-300 µg/paw). To determine whether the peripheral antinociception induced by α-bisabolol was mediated by either the opioid receptors or the NO-cGMP-K+ channels pathway, the effect of pretreatment (10 min before formalin injection) with the appropriate vehicles, naloxone, naltrexone, NG-nitro-l-arginine methyl ester (L-NAME), 1H-[1,2,4]-oxadiazolo[4,2-a]quinoxalin-1-one (ODQ), glibenclamide, glipizide, apamin, charybdotoxin, tetraethylammonium, or 4-aminopyridine on the antinociceptive effects induced by local peripheral α-bisabolol (300 µg/paw) were assessed. α-Bisabolol produced antinociception during both phases of the formalin test. α-Bisabolol antinociception was blocked by L-NAME, ODQ, and all the K+ channels blockers. The peripheral antinociceptive effect produced by α-bisabolol was not blocked by the opioid receptor inhibitors. α-Bisabolol was able to active the NO-cGMP-K+ channels pathway to produce its antinoceptive effect. The participation of opioid receptors in the peripheral local antinociception induced by α-bisabolol is excluded.
Asunto(s)
Analgésicos/farmacología , GMP Cíclico/metabolismo , Sesquiterpenos Monocíclicos/farmacología , Óxido Nítrico/metabolismo , Nocicepción/efectos de los fármacos , Canales de Potasio/metabolismo , Receptores Opioides/metabolismo , Animales , Masculino , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/química , Canales de Potasio/genética , Ratas , Ratas Wistar , Receptores Opioides/química , Receptores Opioides/genéticaRESUMEN
AIMS: Breast cancer-induced chronic pain is usually treated with opioids, but these compounds cause various adverse effects. Transient receptor potential ankyrin 1 (TRPA1) is involved in cancer pain; also, endogenous TRPA1 agonists are associated with cancer pain development. The aim of this study was to observe the antinociceptive effect of a repeated-dose TRPA1 antagonist administration and the production of endogenous TRPA1 agonists and TRPA1 expression in bone tissue in a model of breast cancer pain in mice. Second, we used a sequence reading archive (SRA) strategy to observe the presence of this channel in the mouse bone and in mouse bone cell lines. MAIN METHODS: We used BALB/c mice for experiments. The animals were subjected to the tumor cell inoculation (4 T1 strain). HC-030031 (a TRPA1 antagonist) treatment was done from day 11 to day 20 after tumor inoculation. TRPA1 expression and biochemical tests of oxidative stress were performed in the bone of mice (femur). SRA strategy was used to detect the TRPA1 presence. KEY FINDINGS: Repeated treatment with the TRPA1 antagonist produced an antinociceptive effect. There was an increase in hydrogen peroxide levels, NADPH oxidase and superoxide dismutase activities, but the expression of TRPA1 in the bone tissue was not altered. SRA did not show TRPA1 residual transcription in the osteoblast and osteoclast cell lines, as well as for mice cranial tissue and in mouse osteoclast precursors. SIGNIFICANCE: The TRPA1 receptor is a potential target for the development of new painkillers for the treatment of bone cancer pain.
Asunto(s)
Acetanilidas/farmacología , Huesos/efectos de los fármacos , Dolor en Cáncer/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Neoplasias Mamarias Animales/complicaciones , Nocicepción/efectos de los fármacos , Purinas/farmacología , Canal Catiónico TRPA1/antagonistas & inhibidores , Acetanilidas/administración & dosificación , Animales , Huesos/metabolismo , Dolor en Cáncer/etiología , Dolor en Cáncer/metabolismo , Dolor en Cáncer/patología , Femenino , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Hiperalgesia/patología , Ratones , Ratones Endogámicos BALB C , Purinas/administración & dosificaciónRESUMEN
Spirulina platensis is a "super-food" and has attracted researchers' attention due to its anti-inflammatory, antioxidant, and analgesic properties. Herein, we investigated the antinociceptive effects of Spirulina in different rodent behavior models of inflammatory pain. Male Swiss mice were treated with Spirulina (3-300 mg/kg, p.o.), indomethacin (10 mg/kg, p.o.), or vehicle (0.9% NaCl 10 mL/kg). Behavioral tests were performed with administration of acetic acid (0.6%, i.p.), formalin 2.7% (formaldehyde 1%, i.pl.), menthol (1.2 µmol/paw, i.pl.), cinnamaldehyde (10 nmol/paw, i.pl.), capsaicin (1.6 µg/paw, i.pl.), glutamate (20 µmol/paw, i.pl.), or naloxone (1 mg/kg, i.p.). The animals were also exposed to the rotarod and open field test to determine possible effects of Spirulina on locomotion and motor coordination. The quantitative phytochemical assays exhibited that Spirulina contains significant concentrations of total phenols and flavonoid contents, as well as it showed a powerful antioxidant effect with the highest scavenging activity. Oral administration of Spirulina completely inhibited the abdominal contortions induced by acetic acid (ED50 = 20.51 mg/kg). Spirulina treatment showed significant inhibition of formalin-induced nociceptive behavior during the inflammatory phase, and the opioid-selective antagonist markedly blocked this effect. Furthermore, our data indicate that the mechanisms underlying Spirulina analgesia appear to be related to its ability to modulate TRMP8 and TRPA1, but not by TRPV1 or glutamatergic system. Spirulina represents an orally active and safe natural analgesic that exhibits great therapeutic potential for managing inflammatory pain disorders.
Asunto(s)
Analgésicos/farmacología , Antagonistas de Narcóticos/farmacología , Dolor Nociceptivo/tratamiento farmacológico , Extractos Vegetales/farmacología , Spirulina/química , Canal Catiónico TRPA1/metabolismo , Canales Catiónicos TRPM/metabolismo , Analgésicos/uso terapéutico , Animales , Capsaicina/farmacología , Masculino , Ratones , Naloxona/farmacología , Nocicepción/efectos de los fármacos , Extractos Vegetales/uso terapéuticoRESUMEN
Tissue injury results in the release of inflammatory mediators, including a cascade of nociceptive substances, which contribute to development of hyperalgesia. In addition, during this process endogenous analgesic substances are also peripherally released with the aim of controlling the hyperalgesia. Thus, the present study aimed to investigate whether inflammatory mediators TNF-α, IL-1ß, CXCL1, norepinephrine (NE) and prostaglandin E2 (PGE2) may be involved in the deflagration of peripheral endogenous modulation of inflammatory pain by activation of the opioid system. Thus, male Swiss mice and the paw withdrawal test were used. All substances were injected by the intraplantar route. Carrageenan, TNF-α, CXCL-1, IL1-ß, NE and PGE2 induced hyperalgesia. Selectives µ (clocinamox), δ (naltrindole) and κ (norbinaltorphimine, nor-BNI) and non-selective (naloxone) opioid receptor antagonists potentiated the hyperalgesia induced by carrageenan, TNF-α, CXCL-1 and IL1-ß. In contrast, when the enzyme N-aminopeptidase involved in the degradation of endogenous opioid peptides was inhibited by bestatin, the hyperalgesia was significantly reduced. In addition, the western blotting assay indicated that the expression of the opioid δ receptor was increased after intraplantar injection of carrageenan. The data obtained in this work corroborate the hypothesis that TNF-α, CXCL-1 and IL-ß cause, in addition to hyperalgesia, the release of endogenous substances such as opioid peptides, which in turn exert endogenous control over peripheral inflammatory pain.
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Quimiocina CXCL1 , Hiperalgesia/inducido químicamente , Interleucina-1beta , Nocicepción , Dolor Nociceptivo/inducido químicamente , Péptidos Opioides/metabolismo , Receptores Opioides/metabolismo , Factor de Necrosis Tumoral alfa , Animales , Carragenina , Dinoprostona , Modelos Animales de Enfermedad , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Hiperalgesia/prevención & control , Masculino , Ratones , Antagonistas de Narcóticos/farmacología , Nocicepción/efectos de los fármacos , Dolor Nociceptivo/metabolismo , Dolor Nociceptivo/fisiopatología , Dolor Nociceptivo/prevención & control , Norepinefrina , Receptores Opioides/efectos de los fármacos , Transducción de SeñalRESUMEN
The pro-resolving mechanism is a recently described endogenous process that controls inflammation. The present study evaluated components of this mechanism, including annexin 1 (ANXA1) and the formyl peptide receptor 2/ALX (FPR2/ALX) receptor, in the antihyperalgesic effect induced by electroacupuncture (EA) in an animal model of persistent peripheral inflammation. Male Swiss mice underwent intraplantar (i.pl.) injection with complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed with von Frey monofilaments. Animals were treated with EA (2-10 Hz, ST36-SP6) or subcutaneous BML-111 injection (FPR2/ALX agonist) for 5 consecutive days. In a separate set of experiments, on the first and fifth days after CFA injection, animals received i.pl. WRW4 (FPR2/ALX antagonist) or naloxone (non-selective opioid receptor antagonist) before EA or BML-111 injection. Paw protein levels of FPR2/ALX and ANXA1 were evaluated on the second day after CFA injection by western blotting technique. EA and BML-111 reduced mechanical hyperalgesia. I.pl. naloxone or WRW4 prevented the antihyperalgesic effect induced by either EA or BML-111. EA increased ANXA1 but did not alter FPR2/ALX receptor levels in the paw. Furthermore, i.pl. pretreatment with WRW4 prevented the increase of ANXA1 levels induced by EA. This work demonstrates that the EA antihyperalgesic effect on inflammatory pain involves the ANXA1/FPR2/ALX pro-resolution pathway. This effect appears to be triggered by the activation of FPR2/ALX receptors and crosstalk communication with the opioid system.
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Anexina A1/metabolismo , Electroacupuntura/métodos , Hiperalgesia/terapia , Dolor Nociceptivo/terapia , Receptores de Formil Péptido/metabolismo , Receptores Opioides/metabolismo , Animales , Adyuvante de Freund/toxicidad , Ácidos Heptanoicos/farmacología , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Masculino , Ratones , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Nocicepción/efectos de los fármacos , Dolor Nociceptivo/etiología , Dolor Nociceptivo/metabolismo , Receptores de Formil Péptido/antagonistas & inhibidores , Receptores Opioides/uso terapéuticoRESUMEN
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.
Asunto(s)
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
This study investigated the effects of the protein-free galactomannan obtained from Delonix regia seeds (GM-DR) in an experimental osteoarthritis (OA) model. GM-DR was obtained from water-homogenized endosperms by collection of the supernatant and precipitation with ethanol. The remaining proteins in the galactomannan were removed by alkaline hydrolysis. Weight average molar mass (Mw) of the galactomannan was estimated in 5.8 × 105 g mol-1, presenting mannose:galactose ratio of 2.39:1. Rats received sodium monoiodoacetate (OA groups, 1 mg/25 µL) or saline (sham group) in the right tibio-tarsal joint. GM-DR (30-300 µg) was administered by intra-articular route at days 14 and 21 after OA induction. Hypernociception was evaluated daily by the measurement of the mechanical threshold required to cause joint flexion and paw withdrawal reflex. The 56-day animal groups were euthanized for joint histopahological analysis using the OARSI score system. Lower doses of GM-DR (30 and 100 µg) promoted antinociception from day 15 until the endpoint at day 56. Joint damage was reduced by GM-DR administration (100 µg) in OA-subjected animals, compared to the vehicle-treated OA group (5.9 ± 1.8 vs 19.0 ± 1.8, respectively, p < 0.05). Conclusion: Both antinociception and damage reduction suggest that Delonix regia galactomannan is a promising approach for osteoarthritis therapy.
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Analgésicos/uso terapéutico , Mananos/uso terapéutico , Osteoartritis/tratamiento farmacológico , Dolor/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Fabaceae , Articulaciones del Pie/efectos de los fármacos , Articulaciones del Pie/patología , Galactosa/análogos & derivados , Ácido Yodoacético , Masculino , Nocicepción/efectos de los fármacos , Osteoartritis/inducido químicamente , Osteoartritis/patología , Dolor/inducido químicamente , Dolor/patología , Ratas Wistar , SemillasRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Siparuna guianensis Aublet leaves, known as negramina, are used by indigenous and local communities in Brazil and other countries in the Americas to treat pain and inflammatory diseases. AIM OF THE STUDY: To characterize the chemical constituents and to evaluate the antioxidant, anti-inflammatory, antinociceptive and locomotor activities of the dichloromethane fraction (DF) of S. guianensis leaves. Also, an acute oral toxicity test was accomplished. MATERIAL AND METHODS: The chemical characterization of DF was performed by ultra-high pressure liquid chromatography (UHPLC) analyses coupled with a high-resolution mass spectrometer. The antioxidant potential of DF was investigated using nitric oxide (NO) and hydroxyl radical (OH) scavenging test. The evaluation study of the anti-inflammatory activity was carried out in vitro by NO measurement in stimulated macrophages and, in vivo, by croton oil-induced ear edema, LPS-induced peritonitis, and zymosan-induced arthritis in mice. Different mechanisms of central and peripheral nociception were stimulated by acetic acid-induced writhing, formalin, and tail-flick tests. Besides that, the open field assay was performed. RESULTS: UHPLC analyses of DF showed the presence of a mixture of glycosylated and methoxylated flavonoids. DF was able to scavenge NO and OH radicals in vitro and showed anti-inflammatory activity by inhibiting NO production in LPS-stimulated murine macrophages. Oral administration of DF considerably inhibited the ear edema after croton oil application and reduced the leukocyte infiltrated in LPS-induced peritonitis. In the inflammatory intra-articular zymosan-induced process, DF showed a significant reduction in the inflammatory area and of the cells in the synovial and connective tissues adjacent to the joint. Also, DF was able to reduce the intra-articular edema. In nociception models, the oral administration of DF considerably inhibited the acetic acid-induced writhings. The formalin test showed that DF attenuated the licking time in both phases, which suggested that DF reduce the nociception by central and peripheral mechanisms. In the tail-flick test, DF showed no activity. Besides that, DF did not affect the animal locomotion, and no acute toxicity was observed. CONCLUSIONS: For the first time, the anti-inflammatory and antinociceptive activities of S. guianensis were reported, supporting its ethnopharmacological uses for some inflammatory diseases and painful conditions.