RESUMEN
The discovery of brain therapeutics faces a significant challenge due to the low translatability of preclinical results into clinical success. To address this gap, several efforts have been made to obtain more translatable neuronal models for phenotypic screening. These models allow the selection of active compounds without predetermined knowledge of drug targets. In this review, we present an overview of various existing models within the field, examining their strengths and limitations, particularly in the context of neuropathic pain research. We illustrate the usefulness of these models through a comparative review in three crucial areas: i) the development of novel phenotypic screening strategies specifically for neuropathic pain, ii) the validation of the models for both primary and secondary screening assays, and iii) the use of the models in target deconvolution processes.
Asunto(s)
Neuralgia , Humanos , Neuralgia/tratamiento farmacológico , EncéfaloRESUMEN
Widespread musculoskeletal pain characterizes fibromyalgia (FM), accompanied by sleep, fatigue, and mood problems. Chronic stress and depression play a crucial role in the etiology and pathophysiology of FM. They may contribute to a dysregulation of the central pain mechanisms together with the neuroendocrine and immune systems. Pharmacological treatments are the first-line therapy to reduce the symptoms of FM. The US Food and Drug Administration (FDA) indicated gabapentinoid, pregabalin, duloxetine, and milnacipran for adult patients. An alternative approach is widely used, based on therapies including interventions in patient education, behavioral therapy, exercise, pain management, and a healthy diet. A systematic search was performed on PubMed, MEDLINE, EMBASE, and Web of Science databases. The authors established the selection, inclusion, and exclusion criteria. We found a total of 908 articles. This systematic review will include ten articles selected after excluding duplicates and reading the abstracts and full texts. All studies related the effect of drugs to various symptoms caused by fibromyalgia patients with depression, such as insomnia/sleepiness, depression, suicide, difficulty walking/working, pain, fatigue, and nervousness. Although, we concluded that antidepressant drugs are effective in treating depression and pain in fibromyalgia, further studies are needed to understand the etiology of this disease and to find a combination of therapies to increase tolerability and adherence of the patient to the drug, decreasing the adverse effects.
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Fibromialgia , Dolor Musculoesquelético , Adulto , Humanos , Fibromialgia/tratamiento farmacológico , Antidepresivos/efectos adversos , Fatiga/tratamiento farmacológico , Dolor Musculoesquelético/tratamiento farmacológico , EmpleoRESUMEN
The chemical interaction of nine antiepileptic drugs (tiagabine, gabapentin, pregabalin, lamotrigine, zonisamide, valproic acid, valpromide, vigabatrin, progabide) and two endogenous metabolites (4-aminobutanoic acid, 4-hydroxybutanoic acid) with a model of human GABA transporter 1 (hGAT1) is described using the molecular docking method. To establish the role of hGAT1 in chronic pain, tiagabine, a selective hGAT1 inhibitor, was assessed in the in vivo experiments for its antiallodynic properties in two mouse models of neuropathic pain. Docking analyses performed in this study provided the complex binding energies, specific hydrogen bond components, and hydrogen bond properties such as energies, distances and angles. The data of the docking studies strongly support the assumption that the antiepileptic and analgesic actions of the studied drugs can be at least in part related to the strength of their chemical interactions with hGAT1. In vivo experiments with tiagabine confirmed the involvement of hGAT1 in the regulation of the mechanical nociceptive threshold in neuropathic pain.
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Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacología , Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , Simulación del Acoplamiento Molecular/métodos , Neuralgia/metabolismo , Dimensión del Dolor/efectos de los fármacos , Animales , Anticonvulsivantes/uso terapéutico , Relación Dosis-Respuesta a Droga , Proteínas Transportadoras de GABA en la Membrana Plasmática/química , Humanos , Masculino , Ratones , Neuralgia/tratamiento farmacológico , Ácidos Nipecóticos/metabolismo , Ácidos Nipecóticos/farmacología , Ácidos Nipecóticos/uso terapéutico , Dimensión del Dolor/métodos , Unión Proteica/fisiología , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Estructura Secundaria de Proteína , TiagabinaRESUMEN
The aim of this study was to determine the effects of xanthotoxin (8-methoxypsoralen) on the protective action of 5 various second- and third-generation antiepileptic drugs (i.e., lacosamide, lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock-induced seizure model. Seizure activity was evoked in adult male albino Swiss mice by a current (25mA, 500V, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were determined in the chimney, grip-strength and passive avoidance tests. Total brain antiepileptic drug concentrations were measured to confirm pharmacodynamic nature of observed interactions with xanthotoxin. Results indicate that xanthotoxin (100mg/kg, i.p.) significantly enhanced the anticonvulsant action of lacosamide (P<0.01), oxcarbazepine (P<0.05), pregabalin (P<0.01), and topiramate (P<0.001), but not that of lamotrigine in the maximal electroshock-induced seizure test. Moreover, xanthotoxin (50mg/kg) still significantly potentiated the anticonvulsant action of lacosamide (P<0.05), pregabalin (P<0.05), and topiramate (P<0.001) in this seizure test. Xanthotoxin had no significant impact on total brain concentrations of the studied antiepileptic drugs in mice. Furthermore, combinations of xanthotoxin with oxcarbazepine or topiramate produced no adverse effects. However, xanthotoxin in combination with lacosamide, lamotrigine or pregabalin significantly reduced muscular strength in mice in the grip-strength test. In the chimney test, only the combinations of xanthotoxin with pregabalin significantly impaired motor coordination in mice. In conclusion, the combinations of xanthotoxin with oxcarbazepine and topiramate produce beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced seizure test. A special caution is advised when combining xanthotoxin with pregabalin due to appearance of acute adverse effects.
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Anticonvulsivantes/farmacología , Electrochoque/efectos adversos , Metoxaleno/farmacología , Convulsiones/tratamiento farmacológico , Acetamidas , Animales , Carbamazepina/análogos & derivados , Sinergismo Farmacológico , Fructosa/análogos & derivados , Lacosamida , Lamotrigina , Masculino , Ratones , Oxcarbazepina , Pregabalina , Topiramato , TriazinasRESUMEN
A number of potential analgesic pharmacotherapies developed in preclinical osteoarthritis animal models have failed clinical trials. A possible basis for the lack of translation of preclinical findings to clinical efficacy is the use of a preclinical species that is distinct from that of humans. The current study tested clinical analgesics in a nonhuman primate model of knee osteoarthritis. Following a medial meniscectomy, the animals developed a robust ipsilateral reduction in knee pressure threshold (hyperalgesia) and an ipsilateral reduction in weight bearing (resting pain). The serotonin-noradrenalin reuptake inhibitor duloxetine and opioid morphine increased ipsilateral pressure threshold and weight bearing. By contrast, the anticonvulsant pregabalin did not affect either pressure hyperalgesia or resting pain. The current findings in the nonhuman primate model of osteoarthritis parallel clinical findings, in that duloxetine and opioids are used in the management of osteoarthritis pain whereas pregabalin is not. The current findings also suggest the possible differentiation of pharmacotherapeutics in a nonhuman primate model, of distinguishing potential clinically useful analgesics for the management of osteoarthritic pain from those that are not.
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Analgésicos/farmacología , Osteoartritis de la Rodilla/tratamiento farmacológico , Analgésicos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Femenino , Articulación de la Rodilla/efectos de los fármacos , Articulación de la Rodilla/patología , Articulación de la Rodilla/fisiopatología , Macaca fascicularis , Osteoartritis de la Rodilla/complicaciones , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/fisiopatología , Dolor/complicaciones , Presión , Soporte de PesoRESUMEN
Fibromyalgia is characterized by chronic widespread musculoskeletal pain. A hypofunction in descending pain inhibitory systems is considered to be involved in the chronic pain of fibromyalgia. We examined functional changes in descending pain inhibitory systems in rats with specific alternation of rhythm in temperature (SART) stress, by measuring the strength of diffuse noxious inhibitory controls (DNIC). Hindpaw withdrawal thresholds to mechanical von Frey filament or fiber-specific electrical stimuli by the Neurometer system were used to measure the pain response. To induce DNIC, capsaicin was injected into the intraplantar of the forepaw. SART-stressed rats were established by exposure to repeated cold stress for 4 days. In the control rats, heterotopic intraplantar capsaicin injection increased withdrawal threshold, indicative of analgesia by DNIC. The strength of DNIC was reduced by naloxone (µ-opioid receptor antagonist, intraperitoneally and intracerebroventricularly), yohimbine (α2-adrenoceptor antagonist, intrathecally), and WAY-100635 (5-HT1A receptor antagonist, intrathecally) in the von Frey test. In SART-stressed rats, capsaicin injection did not increase withdrawal threshold in the von Frey test, indicating deficits in DNIC. In the Neurometer test, deficient DNIC in SART-stressed rats were observed only for Aδ- and C-fibers, but not Aß-fibers stimulation. Analgesic effect of intracerebroventricular morphine was markedly reduced in SART-stressed rats compared with the control rats. Taken together, in SART-stressed rats, capsaicin-induced DNIC were deficient, and a hypofunction of opioid-mediated central pain modulation system may cause the DNIC deficit.
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Control Inhibidor Nocivo Difuso , Respuesta al Choque Térmico , Animales , Capsaicina/farmacología , Control Inhibidor Nocivo Difuso/efectos de los fármacos , Respuesta al Choque Térmico/efectos de los fármacos , Hiperalgesia/fisiopatología , Masculino , Morfina/farmacología , Dolor/fisiopatología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Modeling drug interactions is important for illustrating combined drug actions and for predicting the pharmacological and/or toxicological effects that can be obtained using combined drug therapy. AIM: In this study, we propose a new and universal support vector regression (SVR)-based method for the analysis of drug interactions that significantly accelerates the isobolographic analysis. METHODS: Using SVR, a theoretical model of the dose-effect relationship was built to simulate various dose ratios of two drugs. Using the model could then rapidly determine the combinations of doses that elicited equivalent effects compared with each drug used alone. RESULTS: The model that was built can be used for any level of drug effect and can generate classical isobolograms to determine the nature of drug interactions (additivity, subadditivity or synergy), which is of particular importance in the case of novel compounds endowed with a high biological activity for which the mechanism of action is unknown. In addition, this method is an interesting alternative allowing for a meaningful reduction in the number of animals used for in vivo studies. CONCLUSIONS: In a mouse model of toxic peripheral neuropathy induced by a single intraperitoneal dose of oxaliplatin, the usefulness of this SVR method for modeling dose-effect relationships was confirmed. This method may also be applicable during preliminary investigations regarding the mechanism of action of novel compounds.
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Analgésicos/farmacología , Interacciones Farmacológicas , Máquina de Vectores de Soporte , Animales , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Masculino , Ratones , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/farmacología , Oxaliplatino , Enfermedades del Sistema Nervioso Periférico/inducido químicamenteRESUMEN
The nature of the pharmacodynamic interactions of drugs is influenced by the drugs׳ mechanisms of action. It has been hypothesized that drugs with different mechanisms are likely to interact synergistically, whereas those with similar mechanisms seem to produce additive interactions. In this review, we describe an extensive investigation of the published literature on drug combinations of anticonvulsants, the nature of the interaction of which has been evaluated by type I and II isobolographic analyses and the subthreshold method. The molecular targets of antiepileptic drugs (AEDs) include Na(+) and Ca(2+) channels, GABA type-A receptor, and glutamate receptors such as NMDA and AMPA/kainate receptors. The results of this review indicate that the nature of interactions evaluated by type I isobolographic analyses but not by the two other methods seems to be consistent with the above hypothesis. Type I isobolographic analyses may be used not only for evaluating drug combinations but also for predicting the targets of new drugs.