The role of tetrodotoxin-resistant sodium channels in pain states: are they the next target for analgesic drugs?

Neuropathic pain, a persistent chronic pain resulting from damage to the central or peripheral nervous system, is a condition that severely affects the quality-of-life of millions of individuals worldwide. The treatment of neuropathic pain is still an unmet medical need; however, recent advances in our understanding of mechanisms underlying the perception and transmission of painful stimuli offer significant potential for improvement of therapies directed to neuropathic pain. Ectopic activity in damaged and dysfunctional sensory afferents is believed to have a role in the generation and maintenance of neuropathic pain. One of the mechanisms underlying this ectopic firing involves abnormal modulation of voltage-gated sodium channels (NaVs) in the soma and axonal membranes of dorsal root ganglion (DRG) sensory neurons. In fact, NaV blockers have been clinically validated as treatments for neuropathic pain. However, current drugs are weak, non-selective inhibitors of NaVs with dose-limiting CNS and cardiovascular side effects that prevent their use in long-term therapy. Selective NaV tetrodotoxin-resistant channels (NaV 1.8 and NaV 1.9) are expressed exclusively in nociceptive neurons in the DRGs where they play a key role in normal and/or pathological pain sensation, providing an opportunity for the development of novel peripheral analgesics with a better safety profile.