The two-pore domain K(+) channel TRESK is expressed in dorsal root ganglion and trigeminal sensory neurons where it is a major contributor to background K(+) current. TRESK acts as a break to prevent excessive sensory neuron activation and decreases in its expression or function have been involved in neuronal hyperexcitability after injury/inflammation, migraine or altered sensory perception (tingling, cooling and pungent burning sensations). All these effects have implicated this channel in nociception and mechanotransduction. To determine the role of TRESK in sensory transduction, we studied its sensitivity to changes in membrane tension (stretch) in heterologous systems, F-11 cells and trigeminal neurons. Laminar shear stress increased TRESK currents by 22-30%. An increase in membrane tension induced by cell swelling (hypotonic medium) produced a reversible elevation of TRESK currents (39.9%). In contrast, cell shrinkage (hypertonic solution) produced the opposite effect. Membrane crenators or cup-formers produced equivalent effects. In trigeminal sensory neurons, TRESK channels were mechanically stimulated by negative pressure, which led to a 1.51-fold increase in channel open probability. TRESK-like currents in trigeminal neurons were additively inhibited by arachidonic acid, acidic pH and hypertonic stimulation, conditions usually found after tissue inflammation. Our results show that TRESK is modulated by changes in cell membrane tension and/or cell volume. Several key players released during inflammation or tissue injury could modulate sensory neuron activation through small changes in membrane tension.