RESUMO
The responses of the brain to infection, ischemia and trauma share remarkable similarities. These and other conditions of the CNS coordinate an innate immune response marked by activation of microglia, the macrophage-like cells of the nervous system. An important contributor to microglial activation is toll-like receptor 4, a pathogen-associated molecular pattern receptor known to initiate an inflammatory cascade in response to various CNS stimuli. The present review traces new efforts to characterize and control toll-like receptor 4 in inflammatory etiologies of the nervous system.
Assuntos
Doenças do Sistema Nervoso Central/metabolismo , Receptor 4 Toll-Like/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/imunologia , Isquemia Encefálica/metabolismo , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/imunologia , Humanos , Imunidade Inata , Inflamação/imunologia , Inflamação/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Neuroglia/fisiologia , Neuroimunomodulação , Dor/tratamento farmacológico , Dor/imunologia , Dor/metabolismo , Sepse/tratamento farmacológico , Sepse/imunologia , Sepse/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/metabolismo , Transmissão Sináptica , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/antagonistas & inibidoresRESUMO
Opioid-induced proinflammatory glial activation modulates wide-ranging aspects of opioid pharmacology including: opposition of acute and chronic opioid analgesia, opioid analgesic tolerance, opioid-induced hyperalgesia, development of opioid dependence, opioid reward, and opioid respiratory depression. However, the mechanism(s) contributing to opioid-induced proinflammatory actions remains unresolved. The potential involvement of toll-like receptor 4 (TLR4) was examined using in vitro, in vivo, and in silico techniques. Morphine non-stereoselectively induced TLR4 signaling in vitro, blocked by a classical TLR4 antagonist and non-stereoselectively by naloxone. Pharmacological blockade of TLR4 signaling in vivo potentiated acute intrathecal morphine analgesia, attenuated development of analgesic tolerance, hyperalgesia, and opioid withdrawal behaviors. TLR4 opposition to opioid actions was supported by morphine treatment of TLR4 knockout mice, which revealed a significant threefold leftward shift in the analgesia dose response function, versus wildtype mice. A range of structurally diverse clinically-employed opioid analgesics was found to be capable of activating TLR4 signaling in vitro. Selectivity in the response was identified since morphine-3-glucuronide, a morphine metabolite with no opioid receptor activity, displayed significant TLR4 activity, whilst the opioid receptor active metabolite, morphine-6-glucuronide, was devoid of such properties. In silico docking simulations revealed ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. An in silico to in vitro prediction model was built and tested with substantial accuracy. These data provide evidence that select opioids may non-stereoselectively influence TLR4 signaling and have behavioral consequences resulting, in part, via TLR4 signaling.
Assuntos
Analgésicos Opioides/farmacologia , Antígeno 96 de Linfócito/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Analgesia , Animais , Linhagem Celular , Simulação por Computador , Temperatura Alta , Hiperalgesia/psicologia , Bombas de Infusão , Injeções Espinhais , Antígeno 96 de Linfócito/agonistas , Antígeno 96 de Linfócito/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medição da Dor , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/psicologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/antagonistas & inibidores , TransfecçãoRESUMO
Toll-like receptors are an integral part of innate immunity in the central nervous system (CNS); they orchestrate a robust defense in response to both exogenous and endogenous danger signals. Recently, toll-like receptor 4 (TLR4) has emerged as a therapeutic target for the treatment of CNS-related diseases such as sepsis and chronic pain. We herein report a chemical biology approach by using a rationally designed peptide inhibitor to disrupt the TLR4-MD2 association, thereby blocking TLR4 signaling.