Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antitrombinas/efeitos adversos , Dabigatrana/efeitos adversos , Inibidores do Fator Xa/efeitos adversos , Fator Xa/uso terapêutico , Hemorragia/tratamento farmacológico , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Piridonas/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Rivaroxabana/efeitos adversos , Tiazóis/efeitos adversos , Administração Oral , Anticorpos Monoclonais Humanizados/farmacologia , Antitrombinas/uso terapêutico , Perda Sanguínea Cirúrgica/prevenção & controle , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/terapia , Ensaios Clínicos como Assunto , Dabigatrana/antagonistas & inibidores , Dabigatrana/imunologia , Dabigatrana/uso terapêutico , Aprovação de Drogas , Emergências , Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Hemorragia/induzido quimicamente , Humanos , Pirazóis/antagonistas & inibidores , Pirazóis/uso terapêutico , Piridinas/antagonistas & inibidores , Piridinas/uso terapêutico , Piridonas/antagonistas & inibidores , Piridonas/uso terapêutico , Proteínas Recombinantes/farmacologia , Rivaroxabana/antagonistas & inibidores , Rivaroxabana/uso terapêutico , Tiazóis/antagonistas & inibidores , Tiazóis/uso terapêutico , Estados Unidos , United States Food and Drug AdministrationRESUMO
Pyrazole compounds are an intriguing class of compounds with potential analgesic activity; however, their mechanism of action remains unknown. Thus, the goal of this study was to explore the antinociceptive potential, safety and mechanism of action of novel 1-pyrazole methyl ester derivatives, which were designed by molecular simplification, using in vivo and in vitro methods in mice. First, tree 1-pyrazole methyl ester derivatives (DMPE, MPFE, and MPCIE) were tested in the capsaicin test and all presented antinociceptive effect; however the MPClE (methyl 5-trichloromethyl-3-methyl-1H-pyrazole-1-carboxylate) was the most effective. Thus, we selected this compound to assess the effects and mechanisms in subsequent pain models. MPCIE produced antinociception when administered by oral, intraperitoneal, intrathecal and intraplantar routes and was effective in the capsaicin and the acetic acid-induced nociception tests. Moreover, this compound reduced the hyperalgesia in diverse clinically-relevant pain models, including postoperative, inflammatory, and neuropathic nociception in mice. The antinociception produced by orally administered MPClE was mediated by κ-opioid receptors, since these effects were prevented by systemically pre-treatment with naloxone and the κ-opioid receptor antagonist nor-binaltorphimine. Moreover, MPCIE prevented binding of the κ-opioid ligand [(3)H]-CI-977 in vitro (IC50 of 0.68 (0.32-1.4) µM), but not the TRPV1 ([(3)H]-resiniferatoxin) or the α2-adrenoreceptor ([(3)H]-idazoxan) binding. Regarding the drug-induced side effects, oral administration of MPClE did not produce sedation, constipation or motor impairment at its active dose. In addition, MPCIE was readily absorbed after oral administration. Taken together, these results demonstrate that MPClE is a novel, potent, orally active and safe analgesic drug that targets κ-opioid receptors.
Assuntos
Analgésicos/farmacologia , Pirazóis/farmacologia , Receptores Opioides kappa/agonistas , Antagonistas de Receptores Adrenérgicos alfa 2 , Analgésicos/administração & dosagem , Analgésicos/antagonistas & inibidores , Analgésicos/química , Animais , Benzofuranos , Diterpenos , Vias de Administração de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Idazoxano , Masculino , Camundongos , Estrutura Molecular , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medição da Dor , Pirazóis/administração & dosagem , Pirazóis/antagonistas & inibidores , Pirazóis/química , Pirrolidinas , Ensaio Radioligante , Receptores Opioides kappa/antagonistas & inibidores , Canais de Cátion TRPV/efeitos dos fármacos , TrítioRESUMO
The midbrain dorsal periaqueductal gray (dPAG) has an important role in orchestrating anxiety- and panic-related responses. Given the cellular and behavioral evidence suggesting opposite functions for cannabinoid type 1 receptor (CB1) and transient receptor potential vanilloid type-1 channel (TRPV1), we hypothesized that they could differentially influence panic-like reactions induced by electrical stimulation of the dPAG. Drugs were injected locally and the expression of CB1 and TRPV1 in this structure was assessed by immunofluorescence and confocal microscopy. The CB1-selective agonist, ACEA (0.01, 0.05 and 0.5 pmol) increased the threshold for the induction of panic-like responses solely at the intermediary dose, an effect prevented by the CB1-selective antagonist, AM251 (75 pmol). Panicolytic-like effects of ACEA at the higher dose were unmasked by pre-treatment with the TRPV1 antagonist capsazepine (0.1 nmol). Similarly to ACEA, capsazepine (1 and 10 nmol) raised the threshold for triggering panic-like reactions, an effect mimicked by another TRPV1 antagonist, SB366791 (1 nmol). Remarkably, the effects of both capsazepine and SB366791 were prevented by AM251 (75 pmol). These pharmacological data suggest that a common endogenous agonist may have opposite functions at a given synapse. Supporting this view, we observed that several neurons in the dPAG co-expressed CB1 and TRPV1. Thus, the present work provides evidence that an endogenous substance, possibly anandamide, may exert both panicolytic and panicogenic effects via its actions at CB1 receptors and TRPV1 channels, respectively. This tripartite set-point system might be exploited for the pharmacotherapy of panic attacks and anxiety-related disorders.
Assuntos
Pânico/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Canais de Cátion TRPV/fisiologia , Anilidas/administração & dosagem , Anilidas/farmacologia , Animais , Ácidos Araquidônicos/administração & dosagem , Ácidos Araquidônicos/farmacologia , Capsaicina/administração & dosagem , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Cinamatos/administração & dosagem , Cinamatos/farmacologia , Interações Medicamentosas , Estimulação Elétrica/métodos , Masculino , Microinjeções/métodos , Pânico/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/fisiologia , Piperidinas/administração & dosagem , Piperidinas/antagonistas & inibidores , Piperidinas/farmacologia , Pirazóis/administração & dosagem , Pirazóis/antagonistas & inibidores , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismoRESUMO
In this study, we investigated whether spinal noradrenergic and serotonergic systems are involved in the antinociception induced by the novel pyrazolines 3-methyl- and 3-phenyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-1-pyrazole-1-carboxyamide (MPCA and PPCA, respectively), and the pyrazolinone dipyrone in the acetic acid writhing (stretching) test in mice. Intrathecal (i.t.) administration of methysergide (3 and 10 microg) and yohimbine (3 microg), but not of prazosin (0.3 and 1 microg) prevented the antinociceptive action of MPCA and PPCA (500 micromol/kg, s.c.). Dipyrone-induced antinociception (500 micromol/kg, s.c.) was not affected by methysergide or adrenoceptor antagonists. These results suggest that spinal 5-HT receptors and alpha2-adrenoceptors are involved in the antinociception induced by MPCA and PPCA, but not in that elicited by dipyrone.