2002; Peier et al. 2002), and TRPM8 is naturally expressed sensory neurons (Reid et al. 2002; Abe et al. 2005; Kobayashi et al. 2005; Madrid et al. 2006). These TRPM8-expressing sensory neurons project

into the superficial laminae of the spinal cord dorsal horn (Dhaka et al. 2008; Wrigley et al. 2009) that contains cold-sensitive neurons that project into the Inhibitors,research,lifescience,medical spinothalamic tract (Craig and Dostrovsky 2001). Thus, the cold-induced paresthesias after oxaliplatin administration that were accentuated by menthol might be mediated via the activation of TRPM8-expressing innocuous cold receptors, assuming that the receptors access central neurons. Although the Regorafenib nmr precise mechanisms underpinning OPN are still uncertain, this study may serve as an entry point in furthering the mechanistic understanding Inhibitors,research,lifescience,medical of OPN. Oxaliplatin has also been shown to modify intracellular Ca2+ handling within the cell bodies of cultured neurons (Grolleau et al. 2001). A more recent study cited a possible mechanism for some of the oxaliplatin-induced effects that is related to the modification of surface charges around the ion channel: either due to extracellular

Ca2+ chelation or binding of a charged biotransformation product of oxaliplatin Inhibitors,research,lifescience,medical to the channel (Broomand et al. 2009). In addition, the prospective CONcePT study confirmed that OPN could be strongly attenuated by pre- and post-treating patients with Ca2+ and Mg2+ infusions (Gamelin et al. 2008). These findings suggest a mode of action that involves a Ca2+-dependent mechanism in OPN. Therefore, the Ca2+ ion channel TRPM8 appears to be a good candidate for understanding the Ca2+-dependent mechanism in OPN. The TRP ion channel family consists of approximately 28 mammalian Inhibitors,research,lifescience,medical cation channels (Gaudet, 2008; Talavera et al. 2008; Eid and Cortright, 2009) that are involved in a wide range of physiological and pathophysiological

processes including taste, thermosensation, pain, and cell cycle regulation. The TRP ion channels present Inhibitors,research,lifescience,medical a novel mechanism for controlling Ca2+ transients in human neurons and represent potential targets for regulating neurite proliferation and outgrowth. Recent studies have shown that regulating TRPM8 ion channels may be a way of controlling Ca2+ transients in human neurons. We, therefore, hypothesized that oxaliplatin could alter calcium-sensitive voltage-gated Na most channels through a pathway that involves Ca2+ ions that are likely mobilized by TRPM8. Several limitations should be considered in light of our results. Firstly, we did not conduct additional follow-up of CDT after oxaliplatin infusion. Such data would provide a context for the length of time it takes for the CDTs to return to normal and would be very useful from a clinical translation standpoint to approximate the outcome of patients after oxaliplatin infusion. This approach will be incorporated into our next protocol.