Figure 3

(A) Cluster correlations of total gene expression. Cluster correlations of gene expressions among PER1 (period1), PER2, PER3, CRY1 (cryptochrome 1), CRY2, BMAL1 (brain and muscle aryl-hydrocarbon receptor nuclear translocator-like protein-1), TRPV1 (transient receptor potential vanilloid receptor 1), NGF (nerve growth factor), CB1 (cannabinoid receptor 1), CB2, NHE1 (Na/H exchanger 1), NHE3, GDNF (glial derived neurotrophic factor), TAC1 (protachykinin-1), TIM (timeless) and CLOCK (circadian locomotor output cycles kaput). (B) A schematic illustrating the proposed mechanism of esophageal sensitization and the relationship with the circadian-clock system or circadian rhythm in gastroesophageal reflux disease (GERD). Chronic acid injury and inflammation of the esophageal mucosa are initial damages that could induce a local increase in GDNF and NGF, which in turn might trigger pathways leading to persistent collateral sprouting and sensitization. Lowered thermal and/or mechanical thresholds and/or increased density of nerve fibers might be related to TRPV1 expression. The circadian-clock system, including PER1, PER2, CRY2 and BMAL1, may be involved in this elevation of TRPV1 expression through the regulation of protein expression in cell cycle or cell proliferation. Therefore, central sensitization and discomfort express diurnal patterns.