Response to Keszthelyi and Masclee.

Abstract

To the Editor: We thank Keszthelyi and Masclee (1) for their interest in our study and are pleased to note that they agree with our conclusion that transient receptor potential vanilloid 1 (TRPV1) may be an important player in the visceral hypersensitivity of irritable bowel syndrome (IBS) patients (2). The authors comment on the potential role of neuropeptides such as substance P, calictonine-gene-related peptide, and neurokinin A and regret that we did not measure these mediators to obtain a more mechanistic insight into the differential nociceptive responses observed in our study (2). The reasoning is that TRPV1 activation will lead to the release of these neuropeptides from nociceptive nerve fibers and presumably may further activate or sensitize TRPV1. Although this may theoretically be correct, no increase in mucosal substance P levels in IBS compared with healthy controls was measured by Keszthelyi et al. (3) in their recent study, making it less likely that substance P may be involved. To what extent CGRP or neurokinin A may sensitize or upregulate TRPV1 expression is definitely an interesting hypothesis to be further evaluated. We, however, hypothesized that the observed increased pain response to rectal application of capsaicin in the absence of increased expression of TRPV1 would result from TRPV1 sensitization by mast cell mediators rather than by neuropeptides. This hypothesis was based on the abundant evidence in the literature supporting a role for mast cells in IBS, and on our recent clinical study showing clinical improvement following treatment with the mast cell stabilizer and histamine 1 receptor antagonist ketotifen (4). To test this hypothesis, we pewrformed live calcium imaging recordings of submucosal neurons in rectal biopsies, and demonstrated that TRPV1 is sensitized in IBS patients compared with healthy controls, a finding that was mimicked by histamine and reversed by the histamine 1 receptor antagonist pyrilamine. Similar findings were obtained using murine dorsal root ganglia neurons, indicating that histamine, most likely released by mast cells, sensitizes TRPV1 through histamine 1 receptors (5). This was further corroborated by our recent proof-of-concept clinical trial showing improved global symptom relief and reduced abdominal pain in IBS patients during a 12-week treatment with the histamine 1 receptor antagonist ebastine (6). So, although neuropeptides released from afferent nerve fibers may potentially be involved in the sensitization of TRPV1, our recent evidence would rather indicate that mast cell mediators, in particular histamine, may be more likely.