The mechanisms underlying central sensitization following peripheral injury of inflammatory or neuropathic nature are the centre of an intense scientific debate. Potential mechanisms have been classified into 4 categories including synaptic mechanisms, membrane excitability changes, phenotypical changes and morphological reorganization (Sandkühler et al, 2000). We have studied changes in membrane excitability of deep dorsal horn neurones induced by peripheral inflammation. We expected to find enhanced membrane excitability in sensitized neurons. Intraplantar injections of carrageenan produce clear signs of pain hypersensitivity in mice and rats. Spinal cords from these hyperalgesic animals maintained in vitro show significant signs of potentiated segmental reflexes which is interpreted as a sign of central sensitization (Hedo et al 1999). Therefore, we have used the mouse isolated spinal cord in vitro coupled to intracellular techniques to compare the excitability of neurons extracted from naïve and inflamed animals. Cords were always extracted under urethane anaesthesia (2 g/kg, i.p.) following approved protocols. Neurons from treated animals showed large synaptic responses shortly after inflammation (1h) and developed further after a long term inflammation (20h). In contrast, these treated neurones showed biphasic changes in membrane excitability with an increase shortly after inflammation and a decrease in the longer term. These observations lead to the conclusion that membrane excitability plays a complex role in central sensitization. Whereas an increased excitability may be a fast means to boost central sensitization, longer term decreases in excitability may represent a homeostatic correction of an abnormal state of synaptic activity. This new framework opens a window for the study of particular ionic currents and specific ion channels in the dynamic shaping of cell excitability during sensitization. We have shown the contribution of transient and sustained potassium currents to this changing excitability (Rivera-Arconada & Lopez-Garcia 2010). Recently we have also investigated a potential role for the mixed Ih current carried by HCN channels (Rivera-Arconada et al, 2013). Additional evidence from the laboratory suggests that the potassium M current may be involved in shaping excitability during sensitization. These experimental studies will be discussed within the presentation.