A further intriguing possibility is that Hes6 may act to alter the fluctuating expression patterns of neurogenins and Hes proteins that accompany neural differentiation. In neural progenitors, transcription of Hes1, neurogenin 2 and the Notch WZ4002 ligand Deltalike-1 oscillate. On differentiation, Ngn2 and Dll1 expression are maintained at a high level and Hes1 expression is downregulated. Hes6 may play a role in the dynamic interactions between Hes1 and neurogenin that control their reciprocal oscillations, which in turn plays an essential role in progenitor maintenance. We conclude that Hes6 is a mutltifaceted regulator of neuronal differentiation in diverse systems where it plays distinct roles both at the level of regulation of gene expression, and at the level of regulation of proneural protein function. Sensitivity to pain varies greatly across humans and growing evidence suggests that genetic factors might explain part of this variability. Among the few single nucleotide polymorphisms that have been suggested to be associated with pain, one that has recently attracted significant attention is Catechol-Omethyltransferase val158met. COMT is an enzyme that is involved in a number of physiological functions, including the degradation of catecholamine neurotransmitters after their release in the synaptic cleft. The val108/158met SNP is associated with a valine-to-methionine substitution at position 108 or 158, which leads to a four-fold decrease in enzyme activity in met homozygotes, with the heterozygotes demonstrating intermediate activity. The first direct evidence that this polymorphism affects neural processing of pain came from Zubieta and colleagues, who showed that 158met homozygotes were characterized by higher pain sensitivity, diminished regional muopioid system responses to pain, as well as a higher mu-opioid receptor binding potential, compared with heterozygotes. Despite these intriguing results, the existence of an effect of COMT variation on pain sensitivity is still strongly debated, as some subsequent behavioral studies using larger sample size have failed to show a substantial association. In the last few years, evidence produced by several groups has suggested that the effect of COMT polymorphism on pain sensitivity is generally not observed for the initial pain provocations, but rather becomes apparent in later phases of a testing session. Thus, it is possible that the inconsistency in the literature on the effects of COMT is attributable to the delayed onset of this effect, which some studies might have failed to capture. The aim of the present study was to test the hypothesis that the effect of COMT on pain modulation emerges in the setting of a repeated pain challenge, as proposed by Jensen and colleagues. In order to test our hypothesis we reanalyzed the fMRI activations in response to early and late stimuli in a series of repeated heat pain stimulations, using data from three previous experiments from our laboratory.