RESUMEN
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
This work focuses on the δ receptor (DOR), a G protein-coupled receptor (GPCR) belonging to the opioid receptor group. DOR is expressed in numerous tissues, particularly within the nervous system. Our study explores computationally the receptor's interactions with various ligands, including opiates and opioid peptides. It elucidates how these interactions influence the δ receptor response, relevant in a wide range of health and pathological processes. Thus, our investigation aims to explore the significance of DOR as an incoming drug target for pain relief and neurodegenerative diseases and as a source for novel opioid non-narcotic analgesic alternatives. We analyze the receptor's structural properties and interactions using Molecular Dynamics (MD) simulations and Gaussian-accelerated MD across different functional states. To thoroughly assess the primary differences in the structural and conformational ensembles across our different simulated systems, we initiated our study with 1 µs of conventional Molecular Dynamics. The strategy was chosen to encompass the full activation cycle of GPCRs, as activation processes typically occur within this microsecond range. Following the cMD, we extended our study with an additional 100 ns of Gaussian accelerated Molecular Dynamics (GaMD) to enhance the sampling of conformational states. This simulation approach allowed us to capture a comprehensive range of dynamic interactions and conformational changes that are crucial for GPCR activation as influenced by different ligands. Our study includes comparing agonist and antagonist complexes to uncover the collective patterns of their functional states, regarding activation, blocking, and inactivation of DOR, starting from experimental data. In addition, we also explored interactions between agonist and antagonist molecules from opiate and opioid classifications to establish robust structure-activity relationships. These interactions have been systematically quantified using a Quantitative Structure-Activity Relationships (QSAR) model. This research significantly contributes to our understanding of this significant pharmacological target, which is emerging as an attractive subject for drug development.
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Simulación de Dinámica Molecular , Receptores Opioides delta , Receptores Opioides delta/metabolismo , Receptores Opioides delta/química , Humanos , Ligandos , Analgésicos Opioides/farmacología , Analgésicos Opioides/química , Unión Proteica , Conformación ProteicaRESUMEN
PURPOSE: Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex. MATERIALS AND METHODS: Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose. In addition to evaluating locomotor activity and anxiety-related parameters, we also assessed naloxone-induced fentanyl acute withdrawal jumps. We employed real-time quantitative PCR (qPCR) to assess overall gene expression of dopaminergic receptors (Drd1, Drd2, Drd4 and Drd5) and the µ-opioid receptor Oprm1. The levels of epigenetic base modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were assessed on CpG islands of relevant genes. RESULTS: Females had higher locomotor activity than males after chronic fentanyl treatment, and they exhibited higher fentanyl withdrawal jumping behavior induced by naloxone. Females also presented lower Drd4 gene expression and DNA methylation (5mC + 5hmC) in the striatum. We found that locomotor activity and fentanyl withdrawal jumps were negatively correlated with Drd4 methylation and gene expression in the striatum, respectively. CONCLUSIONS: The findings suggested that female mice displayed heightened sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene.
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Fentanilo , Ratones Endogámicos C57BL , Receptores Opioides mu , Caracteres Sexuales , Animales , Fentanilo/farmacología , Masculino , Femenino , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Ratones , Metilación de ADN/efectos de los fármacos , Analgésicos Opioides/farmacología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Locomoción/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Naloxona/farmacología , Conducta Animal/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/genética , Síndrome de Abstinencia a Sustancias/metabolismo , Epigénesis Genética/efectos de los fármacosRESUMEN
Methadone is an effective and long-lasting analgesic drug that is also used in medication-assisted treatment for people with opioid use disorders. Although there is evidence that methadone activates µ-opioid and Toll-like-4 receptors (TLR-4s), its effects on distinct immune cells, including mast cells (MCs), are not well characterized. MCs express µ-opioid and Toll-like receptors (TLRs) and constitute an important cell lineage involved in allergy and effective innate immunity responses. In the present study, murine bone-marrow-derived mast cells (BMMCs) were treated with methadone to evaluate cell viability by flow cytometry, cell morphology with immunofluorescence and scanning electron microscopy, reactive oxygen species (ROS) production, and intracellular calcium concentration ([Ca2+]i) increase. We found that exposure of BMMCs to 0.5 mM or 1 mM methadone rapidly induced cell death by forming extracellular DNA traps (ETosis). Methadone-induced cell death depended on ROS formation and [Ca2+]i. Using pharmacological approaches and TLR4-defective BMMC cultures, we found that µ-opioid receptors were necessary for both methadone-induced ROS production and intracellular calcium increase. Remarkably, TLR4 receptors were also involved in methadone-induced ROS production as it did not occur in BMMCs obtained from TLR4-deficient mice. Finally, confocal microscopy images showed a significant co-localization of µ-opioid and TLR4 receptors that increased after methadone treatment. Our results suggest that methadone produces MCETosis by a mechanism requiring a novel crosstalk pathway between µ-opioid and TLR4 receptors.
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Analgésicos Opioides , Trampas Extracelulares , Humanos , Animales , Ratones , Analgésicos Opioides/farmacología , Receptor Toll-Like 4/metabolismo , Metadona/farmacología , Mastocitos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Médula Ósea/metabolismo , Calcio/metabolismo , Trampas Extracelulares/metabolismo , Receptor Toll-Like 2/metabolismo , Receptores Toll-Like/metabolismoRESUMEN
BACKGROUND: Intravenous infusions of alpha-2 adrenoceptor sedatives and opioids can potentially facilitate surgery in donkeys while standing. Literature on this subject matter is scant. OBJECTIVES: Evaluation of efficacy of sedation from α2-adrenoceptors (dexmedetomidine or xylazine) and butorphanol during ovariectomy in standing donkeys. STUDY DESIGN: Randomised, masked in vivo experiment. METHODS: Thirteen female donkeys were sedated with butorphanol (0.05 mg/kg bwt followed by 0.05 mg/kg bwt/h) IV. Concomitantly, 6 of the 13 jennies were sedated with dexmedetomidine 2.5 mcg/kg bwt followed by 2.5 mcg/kg bwt/h (Dex-B group), while seven jennies were sedated with xylazine 0.5 mg/kg bwt followed by 0.5 mg/kg bwt/h (Xyl-B group). A line block of the left flank and an infiltration block around uterine ligament were performed with lidocaine. While the jennies underwent ovariectomies standing, sedation scores and head height above ground were assessed at 2 and 10 min after sedative boluses and every 10 min thereafter. If sedation was too light or too deep, the dose of dexmedetomidine or xylazine was increased or decreased by 25% of the original infusion rate, while butorphanol infusion rate was constant. Physiological parameters were measured. Normally distributed data were compared using the two-sample t test while repeatedly measured data were tested for differences between and within groups using repeated measures analysis of variance (ANOVA) by ranks followed by a Wilcoxon test with Tukey Honest Significant Difference for multiple testing. Statistical significance was set at p < 0.05. RESULTS: Both Dex-B and Xyl-B caused moderate to marked sedation adequate for ovariectomy in donkeys. Evident sedation was absent by 60 min of termination of infusions. No adverse physiological effects were observed. MAIN LIMITATIONS: Study on ovariectomy cases only, no pharmacokinetic profiling. CONCLUSIONS: Dexmedetomidine or xylazine and butorphanol sedation is feasible for ovariectomy in standing donkeys.
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Butorfanol , Dexmedetomidina , Equidae , Hipnóticos y Sedantes , Ovariectomía , Xilazina , Animales , Dexmedetomidina/administración & dosificación , Dexmedetomidina/farmacología , Femenino , Butorfanol/administración & dosificación , Butorfanol/farmacología , Ovariectomía/veterinaria , Xilazina/farmacología , Xilazina/administración & dosificación , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/farmacología , Infusiones Intravenosas/veterinaria , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacologíaRESUMEN
Tramadol, an analgesic classified as an "atypical opioid", exhibits both opioid and non-opioid mechanisms of action. This study aimed to explore these mechanisms, specifically the opioid-, cannabinoid-, nitric oxide-, and potassium channel-based mechanisms, which contribute to the peripheral antinociception effect of tramadol, in an experimental rat model. The nociceptive threshold was determined using paw pressure withdrawal. To examine the mechanisms of action, several substances were administered intraplantarly: naloxone, a non-selective opioid antagonist (50 µg/paw); AM251 (80 µg/paw) and AM630 (100 µg/paw) as the selective antagonists for types 1 and 2 cannabinoid receptors, respectively; nitric oxide synthase inhibitors L-NOArg, L-NIO, L-NPA, and L-NIL (24 µg/paw); and the enzyme inhibitors of guanylatocyclase and phosphodiesterase of cGMP, ODQ, and zaprinast. Additionally, potassium channel blockers glibenclamide, tetraethylammonium, dequalinium, and paxillin were used. The results showed that opioid and cannabinoid receptor antagonists did not reverse tramadol's effects. L-NOarg, L-NIO, and L-NPA partially reversed antinociception, while ODQ completely reversed, and zaprinast enhanced tramadol's antinociception effect. Notably, glibenclamide blocked tramadol's antinociception in a dose-dependent manner. These findings suggest that tramadol's peripheral antinociception effect is likely mediated by the nitrergic pathway and sensitive ATP potassium channels, rather than the opioid and cannabinoid pathways.
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Cannabinoides , Tramadol , Ratas , Animales , Analgésicos Opioides/farmacología , Tramadol/farmacología , Tramadol/uso terapéutico , Óxido Nítrico/metabolismo , Ratas Wistar , Canales de Potasio/metabolismo , Hiperalgesia/metabolismo , Nitroarginina , Receptores de Cannabinoides/metabolismo , Gliburida , Analgésicos/farmacología , Analgésicos/uso terapéutico , GMP Cíclico/metabolismo , Cannabinoides/efectos adversosRESUMEN
Chronic opioid intake leads to several brain changes involved in the development of dependence, whereby an early hedonistic effect (liking) extends to the need to self-administer the drug (wanting), the latter being mostly a prefrontal-striatal function. The development of animal models for voluntary oral opioid intake represents an important tool for identifying the cellular and molecular alterations induced by chronic opioid use. Studies mainly in humans have shown that polydrug use and drug dependence are shared across various substances. We hypothesize that an animal bred for its alcohol preference would develop opioid dependence and further that this would be associated with the overt cortical abnormalities clinically described for opioid addicts. We show that Wistar-derived outbred UChB rats selected for their high alcohol preference additionally develop: (i) a preference for oral ingestion of morphine over water, resulting in morphine intake of 15 mg/kg/day; (ii) marked opioid dependence, as evidenced by the generation of strong withdrawal signs upon naloxone administration; (iii) prefrontal cortex alterations known to be associated with the loss of control over drug intake, namely, demyelination, axonal degeneration, and a reduction in glutamate transporter GLT-1 levels; and (iv) glial striatal neuroinflammation and brain oxidative stress, as previously reported for chronic alcohol and chronic nicotine use. These findings underline the relevance of polydrug animal models and their potential in the study of the wide spectrum of brain alterations induced by chronic morphine intake. This study should be valuable for future evaluations of therapeutic approaches for this devastating condition.
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Dependencia de Morfina , Trastornos Relacionados con Sustancias , Humanos , Ratas , Animales , Morfina/efectos adversos , Analgésicos Opioides/farmacología , Ratas Wistar , Naloxona/farmacología , Encéfalo , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Etanol/farmacología , Antagonistas de Narcóticos/farmacologíaRESUMEN
Actualmente, las recomendaciones sobre cuidados paliativos sugieren que éstos se inicien lo más tempranamente posible, con el objetivo de mejorar la calidad de vida del paciente y su familia, con un enfoque biopsicosocial. A pesar de ello, aún persiste en gran parte del personal de salud la idea de que los cuidados paliativos son estrictamente cuidados de fin de vida, por lo que se asocia inconscientemente un paciente en una fase final de su enfermedad. Algunos estudios sugieren que, a pesar de las recomendaciones, la práctica habitual aún mantiene esta costumbre. Adicionalmente, no existe una duración establecida para definir cuánto deberían durar estos cuidados. A continuación, el reporte de un caso de cáncer de tiroides papilar, neoplasia conocida por su curso relativamente benigno, para tratarse de un cáncer, de lenta progresión. Este fue diagnosticado de forma tardía, con metástasis pulmonar e insuficiencia respiratoria como primer motivo de consulta, hace 8 años. Esto contrasta enormemente con la duración promedio de cuidados paliativos alrededor del mundo, que se estima es de 19 días. El reporte de este caso pretende contrastar estas realidades y mostrar un ejemplo de cuidados paliativos prolongados, los beneficios y también posibles consecuencias que éstos han tenido en la vida del paciente.
Currently, recommendations about palliative care suggest that they should be started as early in the course of the disease as possible, with the goal of improving quality of life for patients and their families, with a biopsychosocial approach. Despite this, there's still a pervasive idea among healthcare givers that palliative care is given exclusively at the end of life, thus there's a subconscious association with a patient in the final stages of their disease. Studies suggest that despite recommendations, actual practice maintains this custom. Additionally, there's no definitive duration for palliative care. The following is a case report of papillary thyroid cancer, a disease known for a relatively benign course compared to other forms of cancer, and slow progression. This disease was diagnosed in an advanced stage, with pulmonary metastasis and respiratory failure, 8 years ago. This is in stark contrast with the average duration of palliative care around the world, which is estimated to be 19 days. This report intends to highlight this difference and show an example of prolonged palliative care, the benefits and potential consequences that these may have had on the patient's life.
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Humanos , Masculino , Adulto , Cuidados Paliativos , Neoplasias de la Tiroides/complicaciones , Neoplasias de la Tiroides/terapia , Manejo del Dolor/métodos , Analgésicos Opioides/farmacologíaRESUMEN
The opioid receptors (OR) regulate food intake. Still, despite extensive pre-clinical research, the overall effects and individual contribution of the mu (MOR), kappa (KOR), and delta (DOR) OR subtypes to feeding behaviors and food intake remain unclear. To address this, we conducted a pre-registered systematic search and meta-analysis of rodent dose-response studies to evaluate the impact of central and peripheral administration of non-selective and selective OR ligands on intake, motivation, and choice of food. All studies had a high bias risk. Still, the meta-analysis confirmed the overall orexigenic and anorexigenic effects of OR agonists and antagonists, respectively. Our results support a larger orexigenic role for central MOR agonists among OR subtypes and that peripheral OR antagonists reduce motivation for and intake of preferred foods. In binary food choice studies, peripheral OR agonists selectively increase the intake of fat-preferred foods; in contrast, they did not increase the intake of sweet carbohydrate-preferred foods. Overall, these data support that OR regulation of intake, motivation, and choice is influenced by food macronutrient composition.
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Motivación , Receptores Opioides , Analgésicos Opioides/farmacología , Ingestión de Alimentos , Conducta Alimentaria , Ligandos , Receptores Opioides muRESUMEN
Studies performed in a mouse model of chronic inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) have shown that constitutive activation of the endogenous opioid signaling, besides serving as a mechanism of endogenous analgesia that tonically represses pain sensitization, also generates a state of endogenous opioid dependence. Since species-related differences concerning pain biology and addictive behaviors occur between mice and rats, the present study explored whether the coexistence of endogenous opioid analgesia and endogenous opioid dependence also characterizes a homologous rat model. To this aim, CFA-injured Wistar rats were treated with either 3 mg/kg or 10 mg/kg of the opioid receptor inverse agonist naltrexone (NTX) during the pain remission phase and monitored for 60 min for possible withdrawal behaviors. At 3 mg/kg, NTX, besides inducing the reinstatement of mechanical allodynia, also caused a distinct appearance of ptosis, with slight but nonsignificant changes to the occurrence of teeth chatters and rearing. On the other hand, 10 mg/kg of NTX failed to unmask pain sensitization and induced significantly lower levels of ptosis than 3 mg/kg. Such an NTX-related response pattern observed in the rat CFA model seems to differ substantially from the pattern previously described in the mouse CFA model. This supports the knowledge that mice and rats are not identical in terms of pharmacological response and stresses the importance of choosing the appropriate species for preclinical pain research purposes depending on the scientific question being asked.
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Dolor Crónico , Trastornos Relacionados con Opioides , Ratas , Ratones , Animales , Analgésicos Opioides/farmacología , Agonismo Inverso de Drogas , Ratas Wistar , Inflamación/tratamiento farmacológico , Dolor Crónico/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Péptidos Opioides/uso terapéutico , Naltrexona/farmacología , Naltrexona/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
Despite the available knowledge on underlying mechanisms and the development of several therapeutic strategies, optimal management of postoperative pain remains challenging. This preclinical study hypothesizes that, by promoting an anti-inflammatory scenario, pre-emptive administration of IMT504, a noncoding, non-CpG oligodeoxynucleotide with immune modulating properties, will reduce postincisional pain, also facilitating therapeutic opioid-sparing. Male adult Sprague-Dawley rats with unilateral hindpaw skin-muscle incision received pre-emptive (48 and 24 hours prior to surgery) or postoperative (6 hours after surgery) subcutaneous vehicle (saline) or IMT504. Various groups of rats were prepared for pain-like behavior analyses, including subgroups receiving morphine or naloxone, as well as for flow-cytometry or quantitative RT-PCR analyses of the spleen and hindpaws (for analysis of inflammatory phenotype). Compared to vehicle-treated rats, pre-emptive IMT504 significantly reduced mechanical allodynia by 6 hours after surgery, and accelerated recovery of basal responses from 72 hours after surgery and onwards. Cold allodynia was also reduced by IMT504. Postoperative administration of IMT504 resulted in similar positive effects on pain-like behavior. In IMT504-treated rats, 3 mg/kg morphine resulted in comparable blockade of mechanical allodynia as observed in vehicle-treated rats receiving 10 mg/kg morphine. IMT504 significantly increased hindpaw infiltration of mesenchymal stem cells, CD4+T and B cells, and caused upregulated or downregulated transcript expressions of interleukin-10 and interleukin-1ß, respectively. Also, IMT504 treatment targeted the spleen, with upregulated or downregulated transcript expressions, 6 hours after incision, of interleukin-10 and interleukin-1ß, respectively. Altogether, pre-emptive or postoperative IMT504 provides protection against postincisional pain, through participation of significant immunomodulatory actions, and exhibiting opioid-sparing effects. PERSPECTIVE: This preclinical study introduces the noncoding non-CpG oligodeoxynucleotide IMT504 as a novel modulator of postoperative pain and underlying inflammatory events. The opioid-sparing effects observed for IMT504 appear as a key feature that could contribute, in the future, to reducing opioid-related adverse events in patients undergoing surgical intervention.
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Analgésicos Opioides , Hiperalgesia , Ratas , Masculino , Animales , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Ratas Sprague-Dawley , Interleucina-10 , Interleucina-1beta , Dolor Postoperatorio/tratamiento farmacológico , Morfina/farmacología , Morfina/uso terapéutico , Oligodesoxirribonucleótidos/uso terapéuticoRESUMEN
The integration between physiologically-based pharmacokinetics (PBPK) models and pharmacodynamics (PD) models makes it possible to describe the absorption, distribution, metabolism and excretion processes of drugs, together with the concentration-response relationship, being a fundamental framework with wide applications in pharmacology. Nevertheless, the enormous complexity of PBPK models and the large number of parameters that define them leads to the need to study and understand how the uncertainty of the parameters affects the variability of the models output. To study this issue, this paper proposes a global sensitivity analysis (GSA) to identify the parameters that have the greatest influence on the response of the model. It has been selected as study cases the PBPK models of an inhaled anesthetic and an analgesic, along with two PD interaction models that describe two relevant clinical effects, hypnosis and analgesia during general anesthesia. The subset of the most relevant parameters found adequately with the GSA method has been optimized for the generation of a virtual population that represents the theoretical output variability of various model responses. The generated virtual population has the potential to be used for the design, development and evaluation of physiological closed-loop control systems.
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Analgésicos Opioides , Modelos Biológicos , Analgésicos Opioides/farmacología , Farmacocinética , IncertidumbreRESUMEN
m-Trifluoromethyl diphenyl diselenide (TFDD) has antinociceptive and antidepressant-like properties and attenuates morphine withdrawal signs in mice. This study investigated if TFDD affects the development of morphine tolerance to its antinociceptive and antidepressant-like effects in mice. We also investigated whether TFDD modulates signaling pathways related to morphine tolerance, including the opioid receptors and some parameters of the nitrergic system. Male adult Swiss mice received morphine alone (5 mg/kg, subcutaneous) and in combination with TFDD (10 mg/kg, intragastric) for 7 days. Mice were subjected to hot plate and forced swim tests on days 1, 3, 5, and 7 of the experimental protocol. Repeated TFDD administrations avoided tolerance development mediated by morphine, including its antinociceptive and antidepressant-like effects. A single morphine dose increased MOR and NOx but decreased iNOS contents in the mouse cerebral cortex. In turn, single morphine and TFDD co-administration restored the MOR and iNOS protein levels. On the other hand, morphine repeated doses enhanced DOR and reduced MOR and NOx contents, whereas the morphine and TFDD association reestablished DOR and NOx levels in the mouse cerebral cortex. In conclusion, some opioid and nitrergic system parameters might contribute to TFDD attenuation of antinociceptive and antidepressant-like tolerance induced by morphine in mice.
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Morfina , Compuestos de Organoselenio , Analgésicos Opioides/farmacología , Animales , Derivados del Benceno/farmacología , Masculino , Ratones , Morfina/farmacología , Compuestos de Organoselenio/farmacología , Receptores Opioides mu/metabolismoRESUMEN
The ethanolic extract from Croton blanchetianus leaves has been shown to have antinociceptive activity in mice. Here, we investigated the antinociceptive activity of an ethyl acetate fraction (EAF) from this extract in mice and the possible pathways involved in the analgesic effect. Adverse effects on behavior and motor coordination were also evaluated. The EAF was characterized by liquid chromatography coupled with mass spectrometry and evaluated (12.5, 25, and 50â mg/kg per os) in the acetic acid-induced abdominal writhing, formalin, hot plate, and tail immersion assays. Naloxone, atropine, glibenclamide, prazosin, or yohimbine was pre-administered to mice to investigate the involved pathways in the formalin test. The open-field, rotarod, and elevated plus-maze tests were used to assess behavior and locomotion. The main components of the EAF were quercetin-3-O-(2-rhamnosyl) rutinoside, hyperoside, quercetin rutinoside pentoside, and quercetin hexoside deoxyhexoside. EAF showed antinociceptive effects in all models and was effective against both neurogenic and inflammatory pain. The reversion of the effects in the formalin test by naloxone and atropine revealed that the EAF acted via the opioid and cholinergic systems. In the open-field test, the behavior of the animals treated with the EAF was like that of control, except at the highest dose, when hypnosis, eyelid ptosis, decreased walking, hygiene, and rearing behaviors were observed. No muscle relaxant effect was observed, but an anxiogenic effect was observed at all doses. This study provides new scientific evidence on the pharmacological properties of C.â blanchetianus leaves and their potential for the development of phytomedicines with analgesic properties.
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Croton , Euphorbiaceae , Analgésicos/farmacología , Analgésicos/uso terapéutico , Analgésicos Opioides/farmacología , Animales , Colinérgicos , Flavonoides , Ratones , Extractos Vegetales/uso terapéutico , Hojas de la PlantaRESUMEN
Moderate exercise reduces arterial pressure (AP) and heart rate (HR) in spontaneously hypertensive rats (SHR) and changes neurotransmission in medullary areas involved in cardiovascular regulation. We investigated if regularly swimming exercise (SW) affects the cardiovascular adjustments mediated by opioidergic neuromodulation in the RVLM in SHR and Wistar-Kyoto (WKY) rats. Rats were submitted to 6 wks of SW. The day after the last exercise bout, α-chloralose-anesthetized rats underwent a cannulation of the femoral artery for AP and HR recordings, and Doppler flow probes were placed around the lower abdominal aorta and superior mesenteric artery. Bilateral injection of endomorphin-2 (EM-2, 0.4 mmol/L, 60 nL) into the RVLM increased MAP in SW-SHR (20 ± 4 mmHg, N = 6), which was lower than in sedentary (SED)-SHR (35 ± 4 mmHg, N = 6). The increase in MAP in SW-SHR induced by EM-2 into the RVLM was similar in SED- and SW-WKY. Naloxone (0.5 mmol/L, 60 nL) injected into the RVLM evoked an enhanced hypotension in SW-SHR (-66 ± 8 mmHg, N = 6) compared to SED-SHR (-25 ± 3 mmHg, N = 6), which was similar in SED- and SW-WKY. No significant changes were observed in HR after EM-2 or naloxone injections into the RVLM. Changes in hindquarter and mesenteric conductances evoked by EM-2 or naloxone injections into the RVLM in SW- or SED-SHR were not different. Mu Opioid Receptor expression by Western blotting was reduced in SW-SHR than in SED-SHR and SW-WKY. Therefore, regularly SW alters the opioidergic neuromodulation in the RVLM in SHR and modifies the mu opioid receptor expression in this medullary area.
Asunto(s)
Analgésicos Opioides/farmacología , Hipertensión/metabolismo , Bulbo Raquídeo/metabolismo , Neuronas/efectos de los fármacos , Condicionamiento Físico Animal , Receptores Opioides mu/metabolismo , Animales , Presión Arterial/efectos de los fármacos , Presión Arterial/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Bulbo Raquídeo/efectos de los fármacos , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Neuronas/metabolismo , Oligopéptidos/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , NataciónRESUMEN
The purpose of this study was to compare the hemodynamic effects of four different combinations of midazolam and opioids in healthy dogs. Twenty-four healthy dogs were divided in four groups (nâ¯=â¯6) using intramuscular midazolam 0.3 mg/kg and morphine 0.3 mg/kg (GMOR), methadone 0.3 mg/kg (GMET), butorphanol 0.2 mg/kg (GBUT) or fentanyl 5 ug/kg (GFEN). Cardiovascular variables were recorded before (TB) and 20 minutes following drug administration (T20) and comprised arterial blood pressure, heart rate and cardiac index. Subsequently, left ventricular work index and total peripheral resistance index were calculated using the previous variables. At the end of the study, data were compared using analysis of variance followed by Tukey test and Friedman followed by Dunn test, all under 5% significance. No differences were found on cardiovascular variables at all times among the groups, which indicates that all combinations provide hemodynamic stability for clinical sedation of healthy dogs. However, a few animals showed paradoxical excitation in GBUT. In conclusion, the association of midazolam with morphine, methadone, butorphanol or fentanyl provides cardiovascular stability and can be used to sedate dogs undergoing cardiovascular examination, although caution is warranted with the use of midazolam with butorphanol due to possible paradoxical excitation.
Asunto(s)
Analgésicos Opioides , Midazolam , Analgésicos Opioides/farmacología , Animales , Butorfanol/farmacología , Perros , Frecuencia Cardíaca , Hemodinámica , Midazolam/farmacologíaRESUMEN
Herein we describe results for the synthesis and synthetic application of 4-amino-3-(arylselenyl)benzenesulfonamides, and preliminary evaluation of antioxidant, anti-edematogenic and antinociceptive properties. This class of compounds was synthesized in good yields by a reaction of commercially available sulfanilamide and diorganyl diselenides in the presence of 10â mol% of I2 . Furthermore, the synthesized compound 4-amino-3-(phenylselenyl)benzenesulfonamide (3 a) was evaluated on complete Freund's adjuvant (CFA)-induced acute inflammatory pain. Dose- and time-response curves of antinociceptive effect of compound 3 a were performed using this experimental model. Also, the effect of compound 3 a was monitored in a hot-plate test to evaluate the acute non-inflammatory antinociception. The open-field test was performed to evaluate the locomotor and exploratory behaviors of mice. Oxidative stress markers, such as glutathione peroxidase activity; reactive species, non-protein thiols, and lipid peroxidation levels were performed to investigate the antioxidant action of compound 3 a. Our findings suggest that the antioxidant effect of compound 3 a may contribute to reducing the nociception and suppress the signaling pathways of inflammation on the local injury induced by CFA. Thus, compound 3 a reduced the paw edema as well as the hyperalgesic behavior in mice, being a promising therapeutic agent for the treatment of painful conditions.
Asunto(s)
Analgésicos Opioides/farmacología , Antiinflamatorios no Esteroideos/farmacología , Compuestos Organometálicos/farmacología , Dolor/tratamiento farmacológico , Compuestos de Selenio/farmacología , Sulfonamidas/farmacología , Analgésicos Opioides/síntesis química , Analgésicos Opioides/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antioxidantes , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Edema/tratamiento farmacológico , Adyuvante de Freund , Inflamación/tratamiento farmacológico , Peroxidación de Lípido/efectos de los fármacos , Locomoción/efectos de los fármacos , Ratones , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Estrés Oxidativo/efectos de los fármacos , Compuestos de Selenio/química , Relación Estructura-Actividad , Sulfonamidas/química , BencenosulfonamidasRESUMEN
Morphine promotes neuroinflammation after NOD-like receptor protein 3 (NLRP3) oligomerization in glial cells, but the capacity of other opioids to induce neuroinflammation and its relationship to the development of analgesic tolerance is unknown. We studied the effects of morphine and fentanyl on NLRP3 inflammasome activation in glial and neuronal cells in the dorsal raphe nucleus (DRN), a region involved in pain regulation. Male Wistar rats received i.p. injections of morphine (10 mg/kg) or fentanyl (0.1 mg/kg) 3 × daily for 7 days and were tested for nociception. Two hours after the last (19th) administration, we analyzed NLRP3 oligomerization, caspase-1 activation and gasdermin D-N (GSDMD-N) expression in microglia (CD11b positive cells), astrocytes (GFAP-positive cells) and neurons (NeuN-positive cells). Tolerance developed to both opioids, but only fentanyl produced hyperalgesia. Morphine and fentanyl activated NLRP3 inflammasome in astrocytes and serotonergic (TPH-2-positive) neurons, but fentanyl effects were more pronounced. Both opioids increased GFAP and CD11b immunoreactivity, caspase-1 and GSDMD activation, indicating pyroptotic cell death. The opioid receptor antagonist (-)-naloxone, but not the TLR4 receptor antagonist (+)-naloxone, prevented microglia activation and NLRP3 oligomerization. Only (+)-naloxone prevented astrocytes' activation. The anti-inflammatory agent minocycline and the NLRP3 inhibitor MCC950 delayed tolerance to morphine and fentanyl antinociception and prevented fentanyl-induced hyperalgesia. MCC950 also prevented opioid-induced NLRP3 oligomerization. In conclusion, morphine and fentanyl differentially induce cell-specific activation of NLRP3 inflammasome and pyroptosis in the DRN through TLR4 receptors in astrocytes and through opioid receptors in neurons, indicating that neuroinflammation is involved in opioid-induced analgesia and fentanyl-induced hyperalgesia after repeated administrations.
Asunto(s)
Fentanilo , Morfina , Analgésicos Opioides/farmacología , Animales , Núcleo Dorsal del Rafe/metabolismo , Fentanilo/farmacología , Masculino , Morfina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas NLR , Piroptosis , Ratas , Ratas Wistar , Receptores Opioides/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
The orexin peptides promote hedonic intake and other reward behaviors through different brain sites. The opioid dynorphin peptides are co-released with orexin peptides but block their effects on reward in the ventral tegmental area (VTA). We previously showed that in the paraventricular hypothalamic nucleus (PVN), dynorphin and not orexin peptides enhance hedonic intake, suggesting they have brain-site-specific effects. Obesity alters the expression of orexin and dynorphin receptors, but whether their expression across different brain sites is important to hedonic intake is unclear. We hypothesized that hedonic intake is regulated by orexin and dynorphin peptides in PVN and that hedonic intake in obesity correlates with expression of their receptors. Here we show that in mice, injection of DYN-A1-13 (an opioid dynorphin peptide) in the PVN enhanced hedonic intake, whereas in the VTA, injection of OXA (orexin-A, an orexin peptide) enhanced hedonic intake. In PVN, OXA blunted the increase in hedonic intake caused by DYN-A1-13. In PVN, injection of norBNI (opioid receptor antagonist) reduced hedonic intake but a subsequent OXA injection failed to increase hedonic intake, suggesting that OXA activity in PVN is not influenced by endogenous opioid activity. In the PVN, DYN-A1-13 increased the intake of the less-preferred food in a two-food choice task. In obese mice fed a cafeteria diet, orexin 1 receptor mRNA across brain sites involved in hedonic intake correlated with fat preference but not caloric intake. Together, these data support that orexin and dynorphin peptides regulate hedonic intake in an opposing manner with brain-site-specific effects.
Asunto(s)
Dinorfinas , Núcleo Hipotalámico Paraventricular , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacología , Animales , Encéfalo/metabolismo , Dinorfinas/metabolismo , Dinorfinas/farmacología , Ratones , Obesidad/metabolismo , Orexinas/metabolismoRESUMEN
Opioids are potent painkillers, however, their therapeutic use requires close medical monitoring to diminish the risk of severe adverse effects. The G-protein biased agonists of the µ-opioid receptor (MOR) have shown safer therapeutic profiles than non-biased ligands. In this work, we performed extensive all-atom molecular dynamics simulations of two markedly biased ligands and a balanced reference molecule. From those simulations, we identified a protein-ligand interaction fingerprint that characterizes biased ligands. Then, we built and virtually screened a database containing 68,740 ligands with proven or potential GPCR agonistic activity. Exemplary molecules that fulfill the interacting pattern for biased agonism are showcased, illustrating the usefulness of this work for the search of biased MOR ligands and how this contributes to the understanding of MOR biased signaling.