RESUMEN

The development of new analgesics has been challenging. Candidate drugs often have limited clinical utility due to side effects that arise because many drug targets are involved in signaling pathways other than pain transduction. Here, we explored the potential of targeting protein-protein interactions (PPIs) that mediate pain signaling as an approach to developing drugs to treat chronic pain. We reviewed the approaches used to identify small molecules and peptide modulators of PPIs and their ability to decrease pain-like behaviors in rodent animal models. We analyzed data from rodent and human sensory nerve tissues to build associated signaling networks and assessed both validated and potential interactions and the structures of the interacting domains that could inform the design of synthetic peptides and small molecules. This resource identifies PPIs that could be explored for the development of new analgesics, particularly between scaffolding proteins and receptors for various growth factors and neurotransmitters, as well as ion channels and other enzymes. Targeting the adaptor function of CBL by blocking interactions between its proline-rich carboxyl-terminal domain and its SH3-domain-containing protein partners, such as GRB2, could disrupt endosomal signaling induced by pain-associated growth factors. This approach would leave intact its E3-ligase functions, which are mediated by other domains and are critical for other cellular functions. This potential of PPI modulators to be more selective may mitigate side effects and improve the clinical management of pain.

Asunto(s)

Analgésicos , Transducción de Señal , Humanos , Animales , Analgésicos/farmacología , Analgésicos/química , Transducción de Señal/efectos de los fármacos , Mapas de Interacción de Proteínas/efectos de los fármacos , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/metabolismo , Dolor/metabolismo , Dolor/tratamiento farmacológico

RESUMEN

In the pursuit of new lead compounds with fewer side effects than opioids, the novel synthetic phytochemical core, 3,3-dibromoflavanone (3,3-DBF), has emerged as a promising candidate for pain management. Acute assays demonstrated dose-dependent central and peripheral antinociceptive activity of 3,3-DBF through the µ-opioid receptor. This study aimed to explore repeated administration effects of 3,3-DBF in mice and compare them with morphine. Mice were treated with 3,3-DBF (30 mg/kg), morphine (6 mg/kg), or vehicle for 10 days, alongside single-treatment groups. Unlike morphine, 3,3-DBF demonstrated antinociceptive effects in the hot plate test without inducing tolerance. Locomotor activity and motor coordination tests (evaluated through the inverted screen and rotarod tests) revealed no significant differences between the 3,3-DBF-treated and control groups. The gastrointestinal transit assay indicated that 3,3-DBF did not induce constipation, in contrast to morphine. Furthermore, withdrawal signs assessed with the Gellert-Holtzman scale were not comparable to morphine. Additionally, 3,3-DBF exhibited antidepressant-like activity, reducing immobility time in the forced swimming and tail suspension tests, akin to imipramine. In summary, 3,3-DBF demonstrated antinociceptive effects without inducing tolerance or dependence and exhibited antidepressant properties. These findings highlight the potential of 3,3-DBF as a promising therapeutic agent for pain management and its comorbidities, offering advantages over morphine by minimizing side effects.

Asunto(s)

Analgésicos , Antidepresivos , Flavonoides , Morfina , Animales , Morfina/farmacología , Morfina/uso terapéutico , Ratones , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Antidepresivos/química , Masculino , Analgésicos/farmacología , Analgésicos/uso terapéutico , Analgésicos/química , Flavonoides/farmacología , Flavonoides/uso terapéutico , Flavonoides/química , Dolor/tratamiento farmacológico , Manejo del Dolor/métodos , Actividad Motora/efectos de los fármacos

RESUMEN

Eugenia flavescens is a species cultivated in Brazil for food purposes. Given the potential application of essential oils from plants of the genus Eugenia, this study was carried out to investigate the chemical composition, acute toxicity, antioxidant, antinociceptive, gastroprotective activities, and possible mechanisms of action of the essential oil from the leaves of E. flavescens (EOEf). The EOEf was extracted by hydrodistillation, and the chemical composition was obtained using gas chromatography-mass spectrometry. The antioxidant activity was evaluated, as well as the acute toxicity and the antinociceptive and anti-inflammatory effects in mice. In addition, the gastroprotective effect was investigated using an acute gastric lesion model, considering possible mechanisms of action. The major components found in the EOEf were guaiol (19.97%), germacrene B (12.53%), bicyclogermacrene (11.11%), and E-caryophyllene (7.53%). The EOEf did not cause signs of toxicity in the acute oral toxicity test and showed in vitro antioxidant activity with IC50 ranging from 247.29 to 472.39 µg/mL in the tests ABTS and DPPH. In the nociceptive test, EOEf showed a 72.05% reduction in nociception at a dose of 100 mg/kg. In evaluating the anti-inflammatory effect, the essential oil inhibited paw edema by 95.50% and 97.69% at doses of 50 and 100 mg/kg. The results showed that EOEf has a gastroprotective effect, acting through the sulfhydryl compounds (-SH), nitric oxide (NO), and synthesis PGE2 pathways. The results suggested that EOEf is a promising source of constituents with antioxidant, antinociceptive, anti-inflammatory, and gastroprotective properties with application in the food and pharmaceutical industries.

Asunto(s)

Analgésicos , Antiinflamatorios , Antioxidantes , Etanol , Eugenia , Inflamación , Aceites Volátiles , Dolor , Hojas de la Planta , Úlcera Gástrica , Animales , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/inducido químicamente , Aceites Volátiles/farmacología , Ratones , Hojas de la Planta/química , Analgésicos/farmacología , Analgésicos/aislamiento & purificación , Antioxidantes/farmacología , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Dolor/tratamiento farmacológico , Dolor/inducido químicamente , Eugenia/química , Inflamación/tratamiento farmacológico , Brasil , Antiulcerosos/farmacología , Antiulcerosos/aislamiento & purificación , Femenino

RESUMEN

Ayapana triplinervis (M.Vahl) R.M.King & H.Rob. (Asteraceae), popularly known as japana, is a tropical, aromatic subshrub widely used as tea to combat some diseases. The essential oil was obtained from the leaves by hydrodistillation (3 h), and the chemical composition was analyzed by gas chromatography coupled to mass spectrometry. For in vivo assays, Mus musculus/Swiss mice were used to evaluate oral acute toxicological (at dose of 2000 mg/kg); peripheral and central analgesic for abdominal contortion (doses of 6.25, 12.5, 25, 50 and 100 mg/kg), hot plate test (12.5, 25, 50, and 100 mg/kg) and formalin (25, 50 and 100 mg/kg); open field test (100 mg/kg); and anti-inflammatory by ear swelling induced by xylene (6.25,12.5, 25, 50, and 100 mg/kg). The yield of A. triplinervis essential oil (AtEO) was 4.6%, and the oxygenated monoterpene 2,5-dimethoxy-p-cymene was the major compound in this study (63.6%). AtEO at a dose of 2,000 mg/kg orally did not change the behavior patterns or mortality of the animals; liver and kidney biochemical levels were similar to the control group, indicating no liver and kidney toxicity. Moreover, AtEO, at doses of 6.25, 12.5, 25, 50, and 100 mg/kg, reduced abdominal contortions by 21%, 54%, 91%, 58%, and 55%, respectively. In the hot plate test, AtEO showed a significant increase in latency time in the 60-min interval at doses of 25 mg/kg (11.3 ± 3.3 s) and 100 mg/kg (11.9 ± 0.9 s). In the first phase of the formalin test, AtEO decreased paw licking time at doses of 25, 50, and 100 mg/kg, with inhibition of 22%, 38%, and 83%; in the second phase, the same doses, decreased licking time with inhibition of 24%, 34%, and 76%. AtEO did not present a significant change in the spontaneous locomotor activity of the animals. Doses of 6.25, 12.5, 25, 50, and 100 mg/kg significantly reduced ear edema induced by topical application of xylene with percentages of 40%, 39%, 54%, 45%, and 45%, respectively. So, AtEO demonstrated low acute oral toxicity and exhibited significant antinociceptive and anti-inflammatory actions, consistent with the use of A. triplinervis in traditional medicine.

Asunto(s)

Analgésicos , Antiinflamatorios , Aceites Volátiles , Animales , Aceites Volátiles/farmacología , Aceites Volátiles/aislamiento & purificación , Ratones , Analgésicos/farmacología , Analgésicos/aislamiento & purificación , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Brasil , Masculino , Relación Dosis-Respuesta a Droga , Asteraceae/química , Dolor/tratamiento farmacológico , Dolor/inducido químicamente , Edema/tratamiento farmacológico , Edema/inducido químicamente , Hojas de la Planta/química , Benzoquinonas/farmacología , Femenino

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Plant vernacular names can provide clues about the popular use of a species in different regions and are valuable sources of information about the culture or vocabulary of a population. Several medicinal plants in Brazil have received names of medicines and brand-name products. AIM OF THE STUDY: The present work aimed to evaluate the chemical composition and pharmacological activity in the central nervous system of three species known popularly by brand names of analgesic, anti-inflammatory, antispasmodic, and digestive drugs. MATERIALS AND METHODS: Hydroethanolic extracts of Alternanthera dentata (AD), Ocimum carnosum (OC), and Plectranthus barbatus (PB) aerial parts were submitted to phytochemical analysis by HPLC-PAD-ESI-MS/MS and evaluated in animal models at doses of 500 and 1000 mg/kg. Mice were tested on hot plate, acetic acid-induced writing, formalin-induced licking, and intestinal transit tests. Aspirin and morphine were employed as standard drugs. RESULTS: The three extracts did not change the mice's response on the hot plate. Hydroethanolic extracts of AD and PB reduced the number of writhes and licking time, while OC was only effective on the licking test at dose of 1000 mg/kg. In addition, AD and OC reduced intestinal transit, while PB increased gut motility. CONCLUSIONS: Pharmacological tests supported some popular uses, suggesting peripheral antinociceptive and anti-inflammatory effects, while the phytochemical analysis showed the presence of several flavonoids in the three hydroethanolic extracts and steroids in PB, with some barbatusterol derivatives described for the first time in the species.

Asunto(s)

Amaranthaceae , Analgésicos , Antiinflamatorios , Parasimpatolíticos , Fitoquímicos , Componentes Aéreos de las Plantas , Extractos Vegetales , Plectranthus , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/química , Analgésicos/farmacología , Analgésicos/química , Ratones , Parasimpatolíticos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/química , Masculino , Amaranthaceae/química , Plectranthus/química , Fitoquímicos/farmacología , Fitoquímicos/análisis , Dolor/tratamiento farmacológico , Ocimum/química , Espectrometría de Masas en Tándem , Brasil , Tránsito Gastrointestinal/efectos de los fármacos

RESUMEN

Metamizole, as known as dipyrone or novaminsulfone is widely used, especially in Latin America, for its analgesic and antipyretic function. However, several countries have banned it due to the risk of agranulocytosis, skin necrosis, and other serious adverse effects. To assess the safety of metamizole compared to other commonly used non-opioid analgesics (paracetamol, ibuprofen, and acetylsalicylic acid). An overview of systematic reviews. The searches were performed in the PubMed, Cochrane Library, Embase, Scopus and LILACS databases. Systematic reviews of randomized and nonrandomized clinical trials with adult patients with mild to moderate pain that assessed the adverse effects of metamizole were included. A methodological quality assessment was performed through ROBIS. The protocol of this systematic review was submitted to the International Prospective Register of Systematic Reviews (Prospero, CRD42021295272). Of 387 identified studies, four were included, with a total of 20,643 participants, all submitted to a single dose by oral, intramuscular, or intravenous route. No study reported a serious adverse effect. However, 60 of 778 patients (7.7%) who used metamizole; 120/828 (14.5%) who used acetylsalicylic acid; 56/443 (12.6%) who used paracetamol; and 27/213 (12.7%) who used ibuprofen had mild adverse effects. A complementary statistical analysis showed that metamizole, at any dose, has a 38.8% lower chance of adverse effects compared to paracetamol and 46.8% compared to acetylsalicylic acid. The results shows that metamizole is a safe drug with evidence of a lower incidence of adverse effects compared to paracetamol and acetylsalicylic acid.

Asunto(s)

Antiinflamatorios no Esteroideos , Dipirona , Dolor , Dipirona/efectos adversos , Dipirona/uso terapéutico , Dipirona/administración & dosificación , Humanos , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/uso terapéutico , Dolor/tratamiento farmacológico , Aspirina/efectos adversos , Aspirina/uso terapéutico , Aspirina/administración & dosificación , Revisiones Sistemáticas como Asunto

RESUMEN

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.

Asunto(s)

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/farmacología

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: In Brazilian popular medicine, Lippia alba leaves are used in teas to treat pain and inflammatory diseases. AIM OF THE STUDY: to evaluate the chemical composition, antinociceptive, and anti-inflammatory activities of Lippia alba essential oil and its major compound geraniol. MATERIAL AND METHODS: Lippia alba leaves were collected in Pará state, Brazil. The leaf essential oil was obtained using a modified Clevenger-type extractor. Then, the oil was analyzed by GC and GC-MS analyses. To evaluate the toxicity of LaEO and geraniol, the doses of 50, 300, and 2000 mg/kg were used in a mouse model. For antinociception tests, abdominal contortion, hot plate, and formalin tests were used; all groups were treated with LaEO and geraniol at doses of 25, 50, and 100 mg/kg; and to evaluate inflammation using the ear edema model. RESULTS: The constituents identified in the highest content were oxygenated monoterpenes: geraniol (37.5%), geranial (6.7%) and neral (3.8%). The animals treated with LaEO and geraniol demonstrated atypical behaviors with aspects of lethargy and drowsiness, characteristics of animals in a state of sedation; the relative weights showed no significant difference compared to the controls. In the abdominal contortion test, LaEO at 25 mg/kg, 50 mg/kg doses, and 100 mg/kg reduced the number of contortions, representing a percentage reduction of 84.64%, 81.23%, and 66.21% respectively. In the hot plate test, LaEO and geraniol increased the latency time at doses of 25, 50, and 100 mg/kg in all test periods; there was no statistical difference between LaEO and geraniol. In the first phase of the formalin test, only doses of 25 mg/kg and 100 mg/kg of LaEO showed significant activity, reducing the latency time by 53.40% and 58.90%. LaEO at doses of 25 mg/kg and 100 mg/kg reduced the size of the edema, demonstrating an anti-inflammatory activity of 59.38% (25 mg/kg) and 50% (100 mg/kg). CONCLUSION: Lippia alba essential oil and geraniol showed central/peripheral analgesic and anti-inflammatory potential and can be used as an alternative or complementary treatment to conventional drugs. More studies are needed to evaluate its action mechanisms and its analgesic effects.

Asunto(s)

Monoterpenos Acíclicos , Analgésicos , Antiinflamatorios , Edema , Lippia , Aceites Volátiles , Hojas de la Planta , Animales , Lippia/química , Aceites Volátiles/farmacología , Aceites Volátiles/química , Brasil , Analgésicos/farmacología , Analgésicos/aislamiento & purificación , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Masculino , Hojas de la Planta/química , Edema/tratamiento farmacológico , Edema/inducido químicamente , Monoterpenos Acíclicos/farmacología , Plantas Medicinales/química , Dolor/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Dimensión del Dolor/efectos de los fármacos

RESUMEN

Chemotherapy-induced peripheral neuropathy (CIPN) and associated pain are prevalent adverse effects of pediatric cancer treatment, significantly affecting the patient's quality of life. Their impact and risk factors have yet to be assessed in our country. This study aimed to assess the prevalence and clinical characteristics of CIPN, as well as to explore associations with patient- and treatment-related variables, within a cohort of Argentinean pediatric oncology patients. Sixty-six patients diagnosed with malignant hematopoietic tumors and receiving the neurotoxic agent vincristine were included in this observational study. Variables analyzed included age, gender, anthropometric measurements, tumor type, chemotherapy treatment, development of pain and other symptoms, severity, and analgesic treatment. The study population consisted of 39 boys and 27 girls. Most patients received two or three neurotoxic drugs. Symptoms consistent with CIPN were identified in 15 children, reflecting a prevalence of 23%. The main symptom was pain in the lower limbs, with some patients reporting jaw or generalized body pain. Pain was categorized as moderate or severe in 60% and 27% of cases, respectively. NSAIDs, anticonvulsants, and/or opioids were prescribed. Among the patient- and treatment-related variables analyzed as potential risk factors, the use of vincristine in conjunction with cytarabine and the administration of a higher number of neurotoxic drugs demonstrated significant association with the development of CIPN. CONCLUSIONS: Combination therapy stands out as a risk factor for clinical CIPN. The high prevalence of moderate/severe pain underscores the importance of close vigilance given its potential to compromise the patient's overall well-being. WHAT IS KNOWN: • Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent adverse effect and dose-limiting factor in pediatric cancer treatment. • Prevalence varies among regions and risk factors are still under study. WHAT IS NEW: • Prevalence of symptomatic CIPN is 23% among pediatric patients undergoing treatment for hematopoietic tumors in a referral hospital in Argentina. Most patients report moderate or severe pain. • Combining vincristine with cytarabine and using a higher number of neurotoxic drugs in combination therapies exhibit significant association with the development of CIPN-related symptoms.

Asunto(s)

Enfermedades del Sistema Nervioso Periférico , Vincristina , Humanos , Masculino , Femenino , Niño , Adolescente , Preescolar , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/epidemiología , Vincristina/efectos adversos , Argentina/epidemiología , Factores de Riesgo , Prevalencia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dolor/tratamiento farmacológico , Dolor/epidemiología , Dolor/etiología , Lactante , Calidad de Vida , Dimensión del Dolor

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Syagrus coronata, a palm tree found in northeastern Brazil, popularly known as licuri, has socioeconomic importance for the production of vegetable oil rich in fatty acids with nutritional and pharmacological effects. Licuri oil is used in traditional medicine to treat inflammation, wound healing, mycosis, back discomfort, eye irritation, and other conditions. AIM OF THE STUDY: The study aimed to evaluate the antinociceptive, anti-inflammatory, and antipyretic effects of treatment with Syagrus coronata fixed oil (ScFO), as well as to determine the safety of use in mice. MATERIALS AND METHODS: Initially, the chemical characterization was performed by gas chromatography-mass spectrometry. Acute single-dose oral toxicity was evaluated in mice at a dose of 2000 mg/kg. Antinociceptive activity was evaluated through abdominal writhing, formalin, and tail dipping tests, and the anti-inflammatory potential was evaluated through the model of acute inflammation of ear edema, peritonitis, and fever at concentrations of 25, 50, and 100 mg/kg from ScFO. RESULTS: In the chemical analysis of ScFO, lauric (43.64%), caprylic (11.7%), and capric (7.2%) acids were detected as major. No mortality or behavioral abnormalities in the mice were evidenced over the 14 days of observation in the acute toxicity test. ScFO treatment decreased abdominal writhing by 27.07, 28.23, and 51.78% at 25, 50, and 100 mg/kg. ScFO demonstrated central and peripheral action in the formalin test, possibly via opioidergic and muscarinic systems. In the tail dipping test, ScFO showed action from the first hour after treatment at all concentrations. ScFO (100 mg/kg) reduced ear edema by 63.76% and leukocyte and neutrophil migration and IL-1ß and TNF-α production in the peritonitis test. CONCLUSION: Mice treated with ScFO had a reduction in fever after 60 min at all concentrations regardless of dose. Therefore, the fixed oil of S. coronata has the potential for the development of new pharmaceutical formulations for the treatment of pain, inflammation, and fever.

Asunto(s)

Analgésicos , Antiinflamatorios , Edema , Aceites de Plantas , Animales , Analgésicos/farmacología , Analgésicos/aislamiento & purificación , Analgésicos/toxicidad , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Aceites de Plantas/farmacología , Masculino , Edema/tratamiento farmacológico , Edema/inducido químicamente , Dolor/tratamiento farmacológico , Peritonitis/tratamiento farmacológico , Antipiréticos/farmacología , Arecaceae/química , Femenino , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Fiebre/tratamiento farmacológico , Fiebre/inducido químicamente , Administración Oral , Modelos Animales de Enfermedad

RESUMEN

BACKGROUND: This study aimed to investigate the analgesic impact of S(+)-ketamine on pain behavior and synovial inflammation in an osteoarthritis (OA) model. METHODS: Animals were grouped as follows: OA-Saline (n = 24) and OA-Ketamine (n = 24), OA induced via intra-articular sodium monoiodoacetate (MIA); a Non-OA group (n = 24) served as the control. On the 7th day post OA induction, animals received either saline or S(+)-ketamine (0.5 mg.kg-1). Behavioral and histopathological assessments were conducted up to day 28. RESULTS: S(+)-ketamine reduced allodynia from day 7 to 28 and hyperalgesia from day 10 to 28. It notably alleviated weight distribution deficits from day 10 until the end of the study. Significant walking improvement was observed on day 14 in S(+)-ketamine-treated rats. Starting on day 14, OA groups showed grip force decline, which was countered by S(+)-ketamine on day 21. However, S(+)-ketamine did not diminish synovial inflammation. CONCLUSION: Low Intra-articular (IA) doses of S(+)-ketamine reduced MIA-induced OA pain but did not reverse synovial histopathological changes. IRB APPROVAL NUMBER: 23115 012030/2009-05.

Asunto(s)

Ketamina , Osteoartritis , Ketamina/administración & dosificación , Animales , Osteoartritis/tratamiento farmacológico , Osteoartritis/inducido químicamente , Ratas , Inyecciones Intraarticulares , Masculino , Analgésicos/administración & dosificación , Ratas Wistar , Dolor/tratamiento farmacológico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inducido químicamente

RESUMEN

Pain has a negative impact on public health, reducing quality of life. Unfortunately, current treatments are not fully effective and have adverse effects. Therefore, there is a need to develop new analgesic compounds. Due to promising results regarding the antinociceptive effect of N-(3-(phenylselanyl)prop-2-in-1-yl)benzamide (SePB), this study aimed to evaluate the participation of the dopaminergic and noradrenergic systems in this effect in mice, as well as its toxicity. To this, the antagonists sulpiride (D2/D3 receptor antagonist, 5 mg/kg), SCH-23390 (D1 receptor antagonist, 0.05 mg/kg), prazosin (α1 adrenergic receptor antagonist, 0.15 mg/kg), yohimbine (α2-adrenergic receptors, 0.15 mg/kg) and propranolol (non-selective ß-adrenergic antagonist, 10 mg/kg) were administered intraperitoneally to mice 15 min before SePB (10 mg/kg, intragastrically), except for propranolol (20 min). After 26 min of SePB administration, the open field test was performed for 4 min to assess locomotor activity, followed by the tail immersion test to measure the nociceptive response. For the toxicity test, animals received a high dose of 300 mg/kg of SePB. SePB showed an increase in the latency for nociceptive response in the tail immersion test, and this effect was prevented by SCH-23390, yohimbine and propranolol, indicating the involvement of D1, α2 and ß-adrenergic receptors in the antinociceptive mechanism of the SePB effect. No changes were observed in the open field test, and the toxicity assessment suggested that SePB has low potential to induce toxicity. These findings contribute to understanding SePB's mechanism of action, with a focus on the development of new alternatives for pain treatment.

Asunto(s)

Propranolol , Calidad de Vida , Ratones , Animales , Propranolol/farmacología , Propranolol/uso terapéutico , Analgésicos/toxicidad , Dolor/tratamiento farmacológico , Norepinefrina , Yohimbina/toxicidad , Yohimbina/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Dopamina , Sulpirida , Receptores Adrenérgicos alfa 2

RESUMEN

OBJECTIVE AND DESIGN: Our aim was to determine an age-dependent role of Nav1.8 and ASIC3 in dorsal root ganglion (DRG) neurons in a rat pre-clinical model of long-term inflammatory pain. METHODS: We compared 6 and 24 months-old female Wistar rats after cutaneous inflammation. We used behavioral pain assessments over time, qPCR, quantitative immunohistochemistry, selective pharmacological manipulation, ELISA and in vitro treatment with cytokines. RESULTS: Older rats exhibited delayed recovery from mechanical allodynia and earlier onset of spontaneous pain than younger rats after inflammation. Moreover, the expression patterns of Nav1.8 and ASIC3 were time and age-dependent and ASIC3 levels remained elevated only in aged rats. In vivo, selective blockade of Nav1.8 with A803467 or of ASIC3 with APETx2 alleviated mechanical and cold allodynia and also spontaneous pain in both age groups with slightly different potency. Furthermore, in vitro IL-1ß up-regulated Nav1.8 expression in DRG neurons cultured from young but not old rats. We also found that while TNF-α up-regulated ASIC3 expression in both age groups, IL-6 and IL-1ß had this effect only on young and aged neurons, respectively. CONCLUSION: Inflammation-associated mechanical allodynia and spontaneous pain in the elderly can be more effectively treated by inhibiting ASIC3 than Nav1.8.

Asunto(s)

Canales Iónicos Sensibles al Ácido , Hiperalgesia , Canal de Sodio Activado por Voltaje NAV1.8 , Dolor , Animales , Femenino , Ratas , Canales Iónicos Sensibles al Ácido/genética , Canales Iónicos Sensibles al Ácido/metabolismo , Canales Iónicos Sensibles al Ácido/farmacología , Analgésicos/uso terapéutico , Ganglios Espinales , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Inflamación/metabolismo , Dolor/tratamiento farmacológico , Dolor/metabolismo , Ratas Sprague-Dawley , Ratas Wistar , Células Receptoras Sensoriales/metabolismo , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo

RESUMEN

Raphanus sativus L. cv. Sango, commonly known as red radish, is widely consumed around the world as a vegetable, but its benefit in pain relief is not sufficiently investigated. This study aimed to evaluate the antinociceptive effects of R. sativus and a possible mechanism of action. An aqueous extract of R. sativus sprouts (AERSS) was investigated by parenteral (10, 30, and 100 mg kg-1, i.p.) and enteral (500 mg kg-1, p.o.) administration in the neurogenic and inflammatory phases of the formalin test, where gastric damage was also evaluated as a possible adverse effect. Ketorolac (5 mg kg-1, i.p.) was used as the reference drug. Endogenous opioid and 5-HT1A serotonin receptors, as well as the cAMP/NO-cGMP pathways, were explored in the study of a possible mechanism of action by using their corresponding antagonists: naloxone, 1 mg kg-1, i.p., WAY100635, 1 mg kg-1, i.p., and enzymatic activators or inhibitors, respectively. Sulforaphane (SFN), a known bioactive metabolite, was analyzed using electroencephalography (EEG) to evidence its central involvement. A significant and dose-dependent antinociceptive activity was observed with the AERSS resembling the antinociceptive effect of the reference drug, with an equivalent significant response with a dose of 500 mg kg-1, p.o. without causing gastric damage. The participation of the endogenous opioid and 5-HT1A serotonin receptors at central and peripheral levels was also observed, with a differential participation of cAMP/NO-cGMP. SFN as one metabolite produced significant changes in the EEG analysis, reinforcing its effects on the CNS. Our preclinical evidence supports the benefits of consuming Raphanus sativus cv. Sango sprouts for pain relief.

Asunto(s)

Analgésicos , Isotiocianatos , Extractos Vegetales , Raphanus , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Analgésicos/farmacología , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Isotiocianatos/farmacología , Dolor/tratamiento farmacológico , Extractos Vegetales/farmacología , Raphanus/química , Receptor de Serotonina 5-HT1A/metabolismo , Receptores Opioides/metabolismo , Transducción de Señal/efectos de los fármacos , Sulfóxidos/farmacología

RESUMEN

BACKGROUND: Osteoarthritis (OA) is a chronic disease that may lead to joint structure degeneration, cartilage destruction, osteophyte formation, subchondral bone disruption, and pain. In this scenario, a higher proportion of the proinflammatory macrophage type 1 (M1) than the anti-inflammatory macrophage type 2 (M2) could be highlighted as a hallmark of OA progression. The balance between these two macrophage types emerges as a new therapeutic target in OA. This study aimed to evaluate the analgesia and macrophage profile in the treatment of experimental osteoarthritis (EOA) with systemic dimethyl fumarate (DMF) or local intra-articular monomethyl fumarate (MMF). RESULTS: DMF via gavage or MMF via intra-articular in the right knee of EOA rats showed improvements in gait parameters and the nociceptive recovery of the mechanical threshold assessment by adapted electronic von Frey treatment on the twenty-first day (long-lasting phase). DMF treatment decreased proinflammatory TNF-α while increasing anti-inflammatory IL-10 cytokines from the macerated capsule on the fifth day (inflammatory phase). MMF treatment showed joint capsule mRNA extraction downregulating iNOS and TNF-α gene expression while upregulating IL-10 and MCP-1. However, CD206 was not significant but higher than untreated EOA rats' joints on the seventh day (inflammatory phase). CONCLUSIONS: Our studies with EOA model induced by MIA suggest a new perspective for human treatment committed with OA based on macrophage polarization as a therapeutic target, switching the proinflammatory profile M1 to the anti-inflammatory profile M2 with DMF systematic or by MMF locally treatment according to the OA severity.

Asunto(s)

Fumaratos , Interleucina-10 , Osteoartritis , Humanos , Ratas , Animales , Factor de Necrosis Tumoral alfa , Osteoartritis/metabolismo , Dolor/tratamiento farmacológico , Dimetilfumarato , Macrófagos/metabolismo , Antiinflamatorios/uso terapéutico

RESUMEN

The aim of this study was to evaluate the effectiveness of photobiomodulation with a 780 nm laser as an adjunct to surgical treatment in the regeneration of bone fractures. Twenty patients diagnosed with open fractures in the lower limbs were selected and randomly divided into two groups: control and LLLT. LLLT parameter: 780 nm, 0.04 cm2 of light beam diameter, 40 mW of power, 10 s per point, 0.4 J of energy, fluence of 10 J/cm2 and irradiance of 1 W/cm2. The evaluated data were: pain, using McGill scale, use of analgesics and anti-inflammatories, levels of cytokines TNF-α, IFN-γ, IL-1ß, IL-10, and IL-17, and bone level regeneration. Data were analyzed using Wilcoxon and Mann-Whitney tests (5%). We can conclude that LLLT was effective as an adjuvant in the bone fracture regeneration process, altered IL-1ß levels, reduced the use of analgesics and anti-inflammatories, reducing the pain pattern throughout the sessions.

Asunto(s)

Citocinas , Fracturas Óseas , Terapia por Luz de Baja Intensidad , Humanos , Proyectos Piloto , Masculino , Citocinas/metabolismo , Femenino , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/terapia , Persona de Mediana Edad , Adulto , Dolor/tratamiento farmacológico , Radiografía , Regeneración Ósea/efectos de los fármacos , Regeneración Ósea/efectos de la radiación , Anciano , Analgésicos/farmacología , Analgésicos/uso terapéutico

RESUMEN

INTRODUCTION: Bothriechis schlegelii is a Crotaline viperid species of Central America and Northern South America. The characteristics of its envenomation have not been well established. We present clinical characteristics of human cases evaluated and treated in a hospital in southwestern Colombia. METHODS: We evaluated data from patients who suffered Bothriechis schlegelii envenomation and were seen at Fundación Valle del Lili Hospital, Cali, Colombia between 2011 and 2022. RESULTS: Eight patients were included, with a median age of 24 years. Snakebites occurred in rural areas. Six (75%) patients were bitten on the upper extremities in relation to the arboreal habits of this animal. The most common symptoms were pain and edema (N = 8, 100%), ecchymoses (N = 2, 25%), and paresthesia (N = 2, 25%). The most common systemic findings were hypofibrinogenemia (N = 8, 100%) and prolonged prothrombin time in five patients (N = 5, 62.5%). All were treated with polyvalent antivenom for Colombian snakes, with a good response and outcome. CONCLUSIONS: Most bite sites from B. schlegelii were on the upper limbs. All patients had both local manifestations, including edema, pain, and systemic effects with hypofibrinogenemia, but none had systemic bleeding. Every patient received antivenom and had favorable outcomes.

Asunto(s)

Afibrinogenemia , Bothrops , Crotalinae , Animales , Humanos , Adulto Joven , Adulto , Colombia/epidemiología , Antivenenos/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/etiología , Edema/etiología

RESUMEN

Fabry disease (FD) is a multisystem lysosomal storage disorder induced by genetic variants in the alpha-galactosidase A (αGalA) gene. Some FD patients have GLA variants with a reduction in overall αGalA enzymatic activity due to mutated proteins with reduced stability, caused by protein misfolding and premature degradation, but the αGalA catalytic activity remains conserved ("amenable" genetic variants). To correct this misfolding and to prevent premature degradation, migalastat, a small iminosugar molecule was developed. We report the clinical characteristics of FD "amenable" cohort patients from Argentina, prior to starting treatment with migalastat. Seventeen Fabry adult patients were recruited from 13 Argentinian Centers; 8 males (47.1%) and 9 females (52.9%) were included. All genotypes included were missense-type "amenables" mutations. Some classic FD typical early manifestations were more frequent in patients with "classic" versus "late-onset" FD phenotype (pain, p=0.002; cornea verticillata, p=0.019). There was a statistically significant difference in estimated glomerular filtration rate in the "classic" versus "late-onset" phenotype (p=0.026) but no difference between genders (p=0.695). Left ventricular mass was similar between genders (p=0.145) and phenotypes (p=0.303). Cardiovascular risk factors were present among "late-onset" females (obesity 50% and smoke 25%). In patients who started "de novo" migalastat, the main indications were (i) heart disease, (ii) kidney damage, and (iii) pain, while in "switched from prior enzyme replacement therapy" patients, the most frequent indication was "patient decision;" this coincides with publications by other authors.

Asunto(s)

1-Desoxinojirimicina/análogos & derivados , Enfermedad de Fabry , Adulto , Humanos , Masculino , Femenino , Enfermedad de Fabry/epidemiología , Enfermedad de Fabry/genética , Enfermedad de Fabry/tratamiento farmacológico , 1-Desoxinojirimicina/uso terapéutico , alfa-Galactosidasa/genética , alfa-Galactosidasa/metabolismo , alfa-Galactosidasa/uso terapéutico , Dolor/inducido químicamente , Dolor/tratamiento farmacológico

RESUMEN

BACKGROUND: The development of analgesic and anti-inflammatory drugs plays a crucial role in modern medicine, aiming to alleviate pain and reduce inflammation in patients. Opioids and nonsteroidal anti-inflammatory drugs are groups of drugs conventionally used to treat pain and inflammation, but a wide range of adverse effects and ineffectiveness in some pathological conditions leads us to search for new drugs with analgesic and anti-inflammatory properties. OBJECTIVES: In this regard, the authors intend to investigate the ((2s,6s)-6-ethyl-tetrahydro-2h-pyran- 2-yl) methanol compound (LS20) on pain and acute inflammation. METHODS: Male Swiss mice were evaluated using acetic acid-induced abdominal writhing, formalin, and tail-flick as models of nociceptive evaluation and edema paw, air pouch and cell culture as models of inflammatory evaluation besides the rotarod test for assessment of motor impairment. RESULTS: The compound showed an effect on the acetic acid-induced abdominal writhing, formalin and tail-flick tests. Studying the mechanism of action, reversion of the antinociceptive effect of the compound was observed from previous intraperitoneal administration of selective and non-selective opioid antagonists on the tail flick test. In addition, the compound induced an antiedematogenic effect and reduced leukocyte migration and the production of pro-inflammatory cytokines in the air pouch model. LS20 was able to maintain cell viability, in addition to reducing cell production of TNF-α and IL-6. CONCLUSION: In summary, the LS20 compound presented an antinociceptive effect, demonstrating the participation of the opioid system and an anti-inflammatory effect related to the inhibition of pro-inflammatory cytokine production. The compound also demonstrated safety at the cellular level.

Asunto(s)

Analgésicos , Antiinflamatorios , Dolor , Piranos , Animales , Masculino , Ratones , Analgésicos/farmacología , Analgésicos/uso terapéutico , Piranos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Dolor/tratamiento farmacológico , Humanos , Inflamación/tratamiento farmacológico , Metanol/química , Ácido Acético , Edema/tratamiento farmacológico , Edema/inducido químicamente , Citocinas/metabolismo

RESUMEN

Malpighia emarginata (Malpighiaceae), popularly known as "acerola", is a tropical and subtropical fruit native to the Americas. Despite its high vitamin C content, which gives it a high antioxidant property, soluble dietary fibers, such as polysaccharides, are also abundant constituents of acerola (10% of the dried fruit). The acerola cold-water soluble (ACWS) fraction presented anti-fatigue and antioxidant effects in vivo and in vitro. To infer further systemic effects of ACWS, this study aimed to investigate the antinociceptive, anti-inflammatory, and antioxidant effects of ACWS in murine models of pain. In formalin-induced nociception, ACWS (0.1, 1, and 10 mg/kg) reduced only the inflammatory phase, and also (10 and 30 mg/kg) attenuated the acetic acid-induced writhing and leukocyte migration in the peritoneal cavity. The mechanical allodynia and paw edema induced by intraplantar injection of carrageenan were greatly reduced by ACWS (10 mg/kg). At the inflammatory pick induced by carrageenan (4 h), ACWS significantly reduced myeloperoxidase activity, TNF-α, IL-1ß, and PGE2 levels, and restored IL-10 levels. ACWS also exhibited antioxidant properties by decreasing lipid hydroperoxides content, increasing GSH levels, and restoring superoxide dismutase and catalase activities in the carrageenan model and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay. Collectively, these results support the antinociceptive, anti-inflammatory, and antioxidant effects of ACWS and reveal a promising candidate for the treatment of inflammatory pain conditions.

Asunto(s)

Malpighiaceae , Pectinas , Animales , Ratones , Pectinas/química , Antioxidantes/análisis , Carragenina , Frutas/química , Polisacáridos/química , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Antiinflamatorios/química , Ácido Ascórbico/análisis , Agua/análisis , Analgésicos/farmacología , Malpighiaceae/química