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Membrane remodeling by inflammatory mediators influences the function of sensory ion channels. The capsaicin- and heat-activated TRPV1 channel contributes to neurogenic inflammation and pain hypersensitivity, in part due to its potentiation downstream of phospholipase C-coupled receptors that regulate phosphoinositide lipid content. Here, we determined the effect of phosphoinositide lipids on TRPV1 function by combining genetic dissection, diet supplementation, behavioral, biochemical, and functional analyses in As capsaicin elicits hot and pain sensation in mammals, transgenic TRPV1 worms exhibit an aversive response to capsaicin. TRPV1 worms with low levels of phosphoinositide lipids display an enhanced response to capsaicin, whereas phosphoinositide lipid supplementation reduces TRPV1-mediated responses. A worm carrying a TRPV1 construct lacking the distal C-terminal domain features an enhanced response to capsaicin, independent of the phosphoinositide lipid content. Our results demonstrate that TRPV1 activity is enhanced when the phosphoinositide lipid content is reduced, and the C-terminal domain is key to determining agonist response TRPV1 is an essential protein for the mechanism whereby noxious stimuli, such as high temperatures and chemicals, cause pain. TRPV1 undergoes sensitization, a process in which inflammatory molecules enhance its response to other stimuli, thereby promoting pain hypersensitivity. Proalgesic agents produced in response to tissue injury activate PLC-coupled receptors and alter the membrane phosphoinositide lipid content. The mechanism by which phosphoinositide lipids modulate TRPV1 function has remained controversial. Determining whether membrane phosphoinositides are positive or negative regulators of TRPV1 function is critical for developing therapeutic strategies to ameliorate TRPV1-mediated inflammatory pain. We address the role of phosphoinositide lipids on TRPV1 function using an approach and report that phosphoinositide lipids reduce TRPV1 activity .