Finally, our results suggest that the effect of COMT on pain might be, albeit genuine, too small to be reliably measured using LY2109761 verbal ratings. In some cases, this effect might be more consistently observed at the brain activity level, since brain activity measures might be considered more proximal phenotypes to perception than subjective reports. In line with this hypothesis is a recent fMRI study, which reported stronger activations within regions of the ‘pain matrix’ in met/met subjects, despite the absence of a difference in pain ratings. On the other hand, the lack of differences in pain ratings in the presence of different patterns of brain activation could also suggest that the COMT genotype might not affect ‘pain processing’ per se, but other brain functions. In fact, as a result of its modulatory role on widespread neuroendocrine and neurotransmitter systems, variation in COMT has been shown to affect brain activity in a wide variety of domains, including attention, working memory and affective regulation, rendering unlikely that pain processing and perception would be specifically targeted. Another possibility, which future studies will need to address, is that COMT might affect neurovascular coupling. In conclusion, COMT appears to affect brain responses to experimentally induced pain, and this effect reveals itself in the context of repeated painful stimulations. However, given our relatively small sample size and unbalanced group Ns, larger and more balanced studies will need to be conducted in order to confirm the validity and generalizability of our observations. Furthermore, future experiments will also need to be specifically designed to test the hypothesis here proposed that the met/met subjects might develop compensatory mechanisms counteracting their putative heightened sensitivity to pain. Colorectal cancers are the second leading cause of death from cancer and the third most commonly diagnosed cancers in the United States. About 5% of the US population will develop CRCs within their lifetime. CRCs are frequently curable by surgical resection when diagnosed at an early stage, while it is difficult to cure when patients are first seen at an advanced stage. Patients with metastatic CRCs have poor outcome with shortened survival. Most CRCs develop in a multistep manner through the adenoma-carcinoma sequence over many years to decades. The process often begins with inactivation of the APC/b-catenin signaling pathway. Accumulation of specific genetic and epigenetic events results in disease progression along three distinct clinicopathologic pathways involving DNA methylation, microsatellite instability, and epigenetic-genetic interactions affecting mutations of KRAS or BRAF oncogenes and the p53 tumor suppressor genes. The molecular mechanisms responsible for progression to CRC metastasis are largely unknown. An early model postulated that metastasis results from rare molecular events.