ABSTRACT
Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord. Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury. Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential (E(anion)) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (gamma-amino butyric acid), as has been shown to occur after peripheral nerve injury. Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E(anion). Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E(anion) shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E(anion). Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia-neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Microglia/metabolism , Neurons/metabolism , Pain/physiopathology , Adenosine Triphosphate/pharmacology , Animals , Anions/metabolism , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/pharmacology , Male , Membrane Potentials/drug effects , Microglia/drug effects , Neurons/drug effects , Posterior Horn Cells/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Rats , Signal Transduction/drug effects , Spinal Cord/cytologyABSTRACT
We investigated the influence of weight and obstructive sleep apnea status on inflammatory and histologic features of the uvula. Tissue samples resected during uvulopalatopharyngoplasty in 11 snorers without obstructive sleep apnea, 11 subjects with obstructive sleep apnea and of similar body mass index and age, and 8 additional obese subjects with obstructive sleep apnea were examined by immunohistochemistry and histologic staining techniques. The frequency and distribution of immune cells, the amount of collagen, and the integrity of the elastin fiber network were evaluated in proximal and distal uvular sections. T cell (CD4+, CD8+) and macrophage counts were higher in the more obese apneic subjects than in the other two groups. In all patients, T cell counts correlated with body mass index, but there was no relationship with the apnea-hypopnea index. A positive correlation was found between elastin fiber network disorganization score and apnea-hypopnea index. We conclude that (1) the amount of inflammatory markers is linked to obesity rather than to sleep-related breathing disorders, and (2) obstructive sleep apnea is associated with a structural alteration of the extracellular matrix of upper airway tissue.