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1.
J Neurosci ; 28(44): 11263-8, 2008 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-18971468

RESUMO

ATP is a known mediator of inflammatory and neuropathic pain. However, the mechanisms by which specific purinergic receptors contribute to chronic pain states are still poorly characterized. Here, we demonstrate that in response to peripheral nerve injury, P2X(4) receptors (P2X(4)R) are expressed de novo by activated microglia in the spinal cord. Using in vitro and in vivo models, we provide direct evidence that P2X(4)R stimulation leads to the release of BDNF from activated microglia and, most likely phosphorylation of the NR1 subunit of NMDA receptors in dorsal horn neurons of the spinal cord. Consistent with these findings, P2X4-deficient mice lack mechanical hyperalgesia induced by peripheral nerve injury and display impaired BDNF signaling in the spinal cord. Furthermore, ATP stimulation is unable to stimulate BDNF release from P2X(4)-deficient mice microglia in primary cultures. These results indicate that P2X(4)R contribute to chronic pain through a central inflammatory pathway. P2X(4)R might thus represent a potential therapeutic target to limit microglia-mediated inflammatory responses associated with brain injury and neurodegenerative disorders.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Microglia/metabolismo , Neuralgia/metabolismo , Traumatismos dos Nervos Periféricos , Receptores Purinérgicos P2/fisiologia , Medula Espinal/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Células COS , Células Cultivadas , Chlorocebus aethiops , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/genética , Dor/genética , Dor/metabolismo , Medição da Dor/métodos , Nervos Periféricos/metabolismo , Receptores Purinérgicos P2/biossíntese , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2X4 , Regulação para Cima/fisiologia
2.
Pain ; 114(3): 386-396, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15777864

RESUMO

The P2X(7) purinoceptor is a ligand-gated cation channel, expressed predominantly by cells of immune origin, with a unique phenotype which includes release of biologically active inflammatory cytokine, interleukin (IL)-1beta following activation, and unique ion channel biophysics observed only in this receptor family. Here we demonstrate that in mice lacking this receptor, inflammatory (in an adjuvant-induced model) and neuropathic (in a partial nerve ligation model) hypersensitivity is completely absent to both mechanical and thermal stimuli, whilst normal nociceptive processing is preserved. The knockout animals were unimpaired in their ability to produce mRNA for pro-IL-1beta, and cytometric analysis of paw and systemic cytokines from knockout and wild-type animals following adjuvant insult suggests a selective effect of the gene deletion on release of IL-1beta and IL-10, with systemic reductions in adjuvant-induced increases in IL-6 and MCP-1. In addition, we show that this receptor is upregulated in human dorsal root ganglia and injured nerves obtained from chronic neuropathic pain patients. We hypothesise that the P2X(7) receptor, via regulation of mature IL-1beta production, plays a common upstream transductional role in the development of pain of neuropathic and inflammatory origin. Drugs which block this target may have the potential to deliver broad-spectrum analgesia.


Assuntos
Neuralgia/imunologia , Neuralgia/fisiopatologia , Receptores Purinérgicos P2/genética , Animais , Western Blotting , Contagem de Células , Doença Crônica , Feminino , Gânglios Espinais/citologia , Expressão Gênica/imunologia , Humanos , Hiperalgesia/imunologia , Hiperalgesia/fisiopatologia , Interleucina-1/genética , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Nociceptores/fisiologia , Precursores de Proteínas/genética , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7
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