Ectopic activity can also contribute to central sensitization, as discussed below. What drives a normally quiet sensory axon, designed only to conduct action potentials, EGFR cancer to begin to initiate action potentials? Nerve injury drastically changes the expression, distribution,

and phosphorylation of many ion channels in sensory neurons leading to changes in intrinsic membrane properties and the generation of membrane potential oscillations resulting in rhythmic firing bursts in the absence of a stimulus. Which ion channels are modified as a direct or indirect consequence of a nerve injury or lesion? As for most neurons, the membrane potential in sensory neurons is largely determined by potassium channels. The two-pore domain

K+ channels TRESK (K2p18.1) and TREK-2 (K2p10.1) represent approximately 85% of K+ background current in DRG neurons (Dobler et al., 2007 and Kang and Kim, 2006) with TRESK being particularly highly expressed in the DRG (Allen Brain Atlas). After injury, TRESK is downregulated by 30%–40% leading to a steady depolarization of the sensory neuronal membrane potential (Tulleuda et al., 2011). However, reduction in potassium leak current cannot be the sole cause of ectopic activity. Subthreshold membrane potential oscillations, find more largely carried by the persistent component of the sodium current, INaP, are frequently seen in injured sensory neurons and may be a major contributor to ectopic spike discharge (Amir et al., 1999). Computer modeling and pharmacological inhibition support the importance of INaP for spontaneous activity in injured neurons (Kovalsky et al., 2009 and Xie et al., 2011), even if the specific molecular identity of the responsible sodium channel remains uncertain. Most likely for injured sensory neurons, this current is generated by non-inactivating Nav1.3- and Nav1.6-mediated currents; but there is also evidence

that Nav1.9 is involved enough (Dib-Hajj et al., 2010, Enomoto et al., 2007 and Herzog et al., 2001). In addition, it is possible that the persistent current is modified by changes in the expression of auxiliary sodium channel β subunits in injured and uninjured fibers, which may alter trafficking and kinetics (Pertin et al., 2005 and Zhao et al., 2011). Membrane potential oscillations, spontaneous activity, and neuropathic pain behavior have also been attributed to the mixed cation current Ih conducted by hyperpolarization-acivated cyclic nucleotide-gated (HCN) channels. Large sensory neurons mainly express HCN1, while small sensory neurons predominantly express HCN2 (Biel et al., 2009, Emery et al., 2011, Momin et al., 2008 and Moosmang et al., 2001). In rodent models of neuropathic pain, low concentrations of the nonspecific HCN antagonist ZD7288 strongly reduce pain behavior and spontaneous firing in injured fibers (Chaplan et al., 2003 and Lee et al., 2005).