, 2006). However, after nerve damage, posttranslational changes, trafficking, and expression changes of TRPV1 also occur. After partial nerve injury, TRPV1 is upregulated in uninjured sensory fibers (Hudson et al., 2001 and Kim et al., 2008), and during diabetic neuropathy changes in the expression of TRPV1 correlate with development of thermal hyper- and hypoalgesia. In addition, TRPV1 begins to be expressed in large myelinated A-fibers (Hong and Wiley, 2005 and Pabbidi et al., 2008), one DAPT of several injury-induced phenotypic shifts in low-threshold sensory neurons. Inhibiting TRPV1 activity or decreasing TRPV1 levels reduces neuropathic

hyperalgesia (Christoph et al., 2006 and Watabiki et al., 2011), and heat hyperalgesia after peripheral neuropathy induced by chemotherapeutic agents is absent in TRPV1 knockout mice (Ta et al., 2010). Other ion channels such as TRPA1, TRPM8, or P2X3 may also be altered during nerve injury and contribute to neuropathic pain hypersensitivity, Selisistat cost but the potential contributions of these ion channels to neuropathic pain are not well understood (Eid et al., 2008, Shinoda et al., 2007 and Xu et al., 2011). TRPV1 is also expressed in sensory nerve axons of peripheral nerves, not only at its peripheral terminal (Weller et al., 2011). Because

Calpain TRPV1 activation threshold is modified by inflammatory mediators from immune cells, and injured nerves contain many macrophages and T cells (Gaudet et al., 2011), it is quite possible, therefore, that axonal TRPV1, just like peripheral terminal TRPV1, may

also become sensitized. Theoretically, a reduction in TRPV1 thermal threshold to levels close to body temperature along the axon could then lead to depolarization and generation of action potentials, producing spontaneous pain (Hoffmann et al., 2008). While TRPV1 is an attractive target for treating neuropathic pain, an unexpected obstacle for the therapeutic use of TRPV1 antagonists is the significant increase in body temperature they produce (Swanson et al., 2005), as well as the risk of damage due to loss of the warning heat pain signal. These complications may be addressed by targeting specific activation sites independent of temperature activation (Szallasi et al., 2007 and Watabiki et al., 2011). A second possibility is to modulate TRPV1 activation threshold by inhibiting kinases known to target TRPV1, such as p38 and PKCε, which are under investigation in neuropathic pain clinical trials and show some efficacy (Anand et al., 2011). Also, repeated low-dose applications of the TRPV1 agonist capsaicin desensitize the channel through phosphorylation and Ca2+-dependent mechanisms (Touska et al., 2011).