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1.
Biol Pharm Bull ; 39(11): 1809-1814, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27803452

RESUMO

Approximately 30% of patients with cancer pain experience concurrent neuropathic pain. Since these patients are not sufficiently responsive to morphine, the development of an effective method of pain relief is urgently needed. Decreased function of the µ opioid receptor, which binds to the active metabolite of morphine M-6-G in the brain, has been proposed as a mechanism for morphine resistance. Previously, we pharmacokinetically examined morphine resistance in mice with neuropathic pain, and demonstrated that the brain morphine concentration was decreased, expression level of P-glycoprotein (P-gp) in the small intestine was increased, and expression level and activity of uridine diphosphate glucuronosyltransferase (UGT)2B in the liver were increased. In order to clarify the mechanism of the increased expression of UGT2B, we examined the phase of neuropathic pain during which UGT2B expression in the liver begins to increase, and whether this increased expression is nuclear receptor-mediated. The results of this study revealed that the increased expression of UGT2B in the liver occurred during the maintenance phase of neuropathic pain, suggesting that it may be caused by transcriptional regulation which was not accompanied by increased nuclear import of pregnane X receptor (PXR).


Assuntos
Glucuronosiltransferase/genética , Fígado/metabolismo , Neuralgia/genética , Animais , Receptor Constitutivo de Androstano , Citocromo P-450 CYP3A/genética , Temperatura Alta , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos ICR , Receptor de Pregnano X , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Esteroides/genética , Nervo Isquiático/lesões
2.
Eur J Pharm Sci ; 92: 298-304, 2016 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-27102159

RESUMO

The chronic administration of morphine to patients with neuropathic pain results in the development of a gradual tolerance to morphine. Although the detailed mechanism of this effect has not yet been elucidated, one of the known causes is a decrease in µ-opioid receptor function with regard to the active metabolite of morphine, M-6-G(morphine-6-glucuronide), in the ventrotegmental area of the midbrain. In this study, the relationship between the concentration of morphine in the brain and its analgesic effect was examined after the administration of morphine in the presence of neuropathic pain. Morphine was orally administered to mice with neuropathic pain, and the relationship between morphine's analgesic effect and its concentration in the brain was analysed. In addition, the expression levels of the conjugation enzyme, UGT2B (uridine diphosphate glucuronosyltransferase), which has morphine as its substrate, and P-gp, which is a transporter involved in morphine excretion, were examined. In mice with neuropathic pain, the concentration of morphine in the brain was significantly decreased, and a correlation was found between this decrease and the decrease in the analgesic effect. It was considered possible that this decrease in the brain morphine concentration may be due to an increase in the expression level of P-gp in the small intestine and to an increase in the expression level and binding activity of UGT2B in the liver. The results of this study suggest the possibility that a sufficient analgesic effect may not be obtained when morphine is administered in the presence of neuropathic pain due to a decrease in the total amount of morphine and M-6-G that reach the brain.


Assuntos
Analgésicos Opioides/farmacocinética , Encéfalo/metabolismo , Tolerância a Medicamentos , Morfina/farmacocinética , Neuralgia/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Analgésicos Opioides/sangue , Analgésicos Opioides/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Glucuronosiltransferase/metabolismo , Intestino Delgado/metabolismo , Fígado/metabolismo , Masculino , Camundongos Endogâmicos ICR , Morfina/sangue , Morfina/uso terapêutico , Derivados da Morfina/metabolismo , Neuralgia/tratamento farmacológico , Nervo Isquiático/lesões
3.
Biol Pharm Bull ; 37(11): 1816-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25212662

RESUMO

Pregabalin, (S)-3-isobutyl-γ-aminobutyric acid (GABA), is a widely used adjuvant therapy for patients with neuropathic pain, which is defined as chronic pain caused by lesions or diseases of the somatosensory nervous system. However, dizziness and somnolence (sleepiness) are common dose-limiting side effects, probably due to excessive sedative effects on higher centers of the central nervous system (CNS) which are involved in the anticonvulsant and analgesic actions of pregabalin. We speculated that transdermal delivery would minimize centrally mediated side effects. To test this idea, we evaluated the analgesic effects of pregabalin delivered through the transdermal route in animal models of neuropathic pain. Transdermally administered pregabalin increased the pain thresholds in response to mechanical stimuli in a partial sciatic nerve ligation model in rats and a spinal nerve ligation model in mice, and surprisingly also in normal animals. It is noteworthy that simple transdermal application of an aqueous solution of pregabalin is effective. This could be a useful treatment option to avoid or minimize the CNS-mediated side effects of orally administered pregabalin.


Assuntos
Analgésicos/administração & dosagem , Neuralgia/tratamento farmacológico , Ácido gama-Aminobutírico/análogos & derivados , Administração Cutânea , Animais , Sistema Nervoso Central , Tontura/prevenção & controle , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Hiperalgesia/tratamento farmacológico , Ligadura , Masculino , Camundongos Endogâmicos ICR , Pregabalina , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/cirurgia , Soluções , Nervos Espinhais/cirurgia , Ácido gama-Aminobutírico/administração & dosagem
4.
ACS Chem Neurosci ; 5(7): 525-32, 2014 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-24738473

RESUMO

Neuropathic pain is a chronic condition resulting from neuronal damage. Pregabalin, the (S)-isomer of 3-isobutyl-γ-aminobutyric acid (GABA), is widely used to treat neuropathic pain, despite the occurrence of central nervous system (CNS)-related side effects such as dizziness and somnolence. Here we describe the pharmacology of novel GABA derivatives containing silicon-carbon bonds, silagaba compounds. Silagaba131, 132, and 161 showed pregabalin-like analgesic activities in animal models of neuropathic pain, but in contrast to pregabalin they did not impair neuromuscular coordination in rotarod tests. Pharmacokinetic studies showed that brain exposure to silagaba compounds was lower than that to pregabalin. Surprisingly, despite their potent analgesic action in vivo, silagaba compounds showed only weak binding to α2-δ protein. These compounds may be useful to study mechanisms of neuropathic pain. Our results also indicate that silagaba132 and 161 are candidates for orally effective treatment of neuropathic pain without CNS-related side effects.


Assuntos
Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Compostos de Organossilício/farmacologia , Ácido gama-Aminobutírico/análogos & derivados , Administração Oral , Analgésicos/efeitos adversos , Analgésicos/farmacocinética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Neuralgia/fisiopatologia , Compostos de Organossilício/efeitos adversos , Compostos de Organossilício/farmacocinética , Limiar da Dor/efeitos dos fármacos , Pregabalina , Desempenho Psicomotor/efeitos dos fármacos , Ensaio Radioligante , Ratos Sprague-Dawley , Ratos Wistar , Teste de Desempenho do Rota-Rod , Tato , Ácido gama-Aminobutírico/efeitos adversos , Ácido gama-Aminobutírico/farmacocinética , Ácido gama-Aminobutírico/farmacologia
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