The esophageal mucosa has two nociceptors that are candidates to mediate heartburn in NERD. These are: a) a capsaicin-sensitive, transient receptor potential vanilloid receptor (TRPV)-1, and b) an amiloride-inhibitable, acid-sensing ion channel (ASIC), subtype 2. Both nociceptor types innervate the esophageal mucosa and are activated by small declines in environmental (intercellular) pH [5,6]. Recently, a role for TRPV-1 was sought in the causation of heartburn during esophageal acid perfusion [7]. This was done by perfusing the esophagus with capsaicin in quantities presumed sufficient to desensitize TRPV-1 and then perfusing with acid to see if it blocked heartburn. The results, however, were negative in that acid still elicited heartburn. From this, one can conclude that heartburn is either not mediated by TRPV-1 or that capsaicin failed to adequately desensitize TRPV-1. We propose to test the hypothesis that capsaicin's failure to block heartburn in these subjects was because the actual nociceptors mediating heartburn are mucosal ASICs rather than TRPV-1. The hypothesis will be tested in a double-blind crossover study designed to determine if esophagal perfusion with the ASIC-inhibitor, amiloride, can block heartburn elicited by acid-perfusion in PPI-complete responders and PPI-partial responders with NERD [8]. The expectation is that, when compared to placebo, amiloride, which readily diffuses across intact esophageal epithelium, will reduce the frequency and both prolong the onset and reduce the severity of heartburn elicitable by esophageal acid perfusion. Such an outcome would provide support for mucosal ASICs, rather than TRPV-1, as mediator of heartburn in NERD, and raise interest in ASICs as a potential therapeutic target for that subset with NERD that are PPI-partial responders.