, 2011 and Momin et al., 2008). Selleckchem SB431542 The evidence for changes in HCN protein and transcript levels after nerve injury are somewhat contradictory and may be explained by somatic versus axonal compartmentalization ( Chaplan et al., 2003 and Jiang et al., 2008). However, even if expression changes are minimal, alterations in cAMP levels could contribute to modified Ih densities, and it is conceivable that inhibitors that block adenyl cyclase exert some of their analgesic action in neuropathic pain models

in the periphery by reducing HCN channel sensitization ( Wang et al., 2011). How does Ih contribute to generating ectopic discharges? Because of activation by hyperpolarizing potentials, HCN channels

are also an important component for membrane FRAX597 potential oscillations in various neuronal networks ( Biel et al., 2009). Especially in concert with low-threshold T-type calcium channels, neurons can display repetitive firing patterns, where hyperpolarization leads to activation of Ih, slowly depolarizing the membrane potential until a Ca2+ spike carried by T-type calcium channels is initiated, further depolarizing the potential and triggering a series of Na2+ spikes. The depolarization inactivates Ih until the train of action potentials is followed by a hyperpolarizing overshoot, which opens HCN channels and the cycle can repeat ( Biel et al., 2009). This model also explains the observed analgesic effect of peripherally applied T-type antagonists in neuropathic pain models ( Barton et al.,

2005 and Dogrul et al., 2003). Given their contribution to generator potentials in the peripheral terminal and action potentials in the axon, it is not surprising that voltage-gated sodium channels (VGSC) have been a prime target of investigation and therapeutic approaches for neuropathic pain (Devor, 2006 and Dib-Hajj et al., 2010). Nav1.8 is mainly expressed by A- and C-fiber nociceptors, Nav1.9 is selective for a subset of C-fibers, whereas Nav1.1 and Nav1.6 are found mostly in nonnociceptive neurons (Fukuoka et al., 2008 and Fukuoka and Noguchi, 2011). Nav1.7 seems to be Etomidate expressed universally in all sensory neurons, but clearly plays an important role in nociception, as indicated by various monogenetic disorders affecting this channel, including gain of function mutations in Nav1.7 that result in ectopic firing of C-fibers in the absence of nerve injury and spontaneous pain conditions (Cox et al., 2006, Dib-Hajj et al., 2010 and Faber et al., 2011). Nav1.3 is usually only expressed during development (Waxman et al., 1994); however, nerve injury drastically changes this expression profile and expression of Nav1.3 returns in adult sensory neurons (Fukuoka et al., 2008 and Waxman et al., 1994). Notably, Nav1.