NaV Channel Blockers for Pain Research Explorer Kit

Voltage-dependent sodium channels (Na_V) have functions in most electrically active cells and are vital for the propagation of action potentials in these cells. Na_V channel inhibiting drugs have long been used as analgesic drugs with relatively mild side-effects and safe pharmacological profiles. The mechanism of analgesia by Na_V channel blockage has been extensively studied.

Four Na_V channel subtypes involved in pain are Na_V1.3, 1.7, 1.8 and 1.9. Na_V1.8 and 1.9 are referred to as tetrodotoxin (TTX)-resistant channels and are implicated in pain relief because action potentials in nociceptive neurons are characteristically also resistant to TTX. The relatively depolarized voltage-dependence of inactivation of Na_V1.8 also allows these channels to contribute to action potential generation even at depolarized membrane potentials as may occur following nerve injury or pain signaling. Importantly, Na_V1.8 was found to be almost exclusively localized to nociceptive DRG neurons – mainly in small diameter unmyelinated C-fibers, but also in some medium diameter, thinly myelinated Aδ-fibers. Na_V1.9 channels are exclusively expressed in C-fibers. Studies suggest that it is responsible for the persistent component of TTX-r currents that are found in nociceptive DRG neurons, having very slow kinetics and a large window current due to a hyperpolarised voltage-dependence of activation compared to inactivation. Na_V1.9 knockout mice have no neuropathic pain phenotype, but do show reduced hypersensitivity to inflammatory stimuli. Na_V1.7 is also expressed in DRG cells, but unlike Na_V1.8 and 1.9, it is sensitive to TTX and is expressed in both nociceptive and non-nociceptive peripheral neurons. Na_V1.7 channels have unusually slow kinetics of open-state and closed-state inactivation, and these unusual gating properties may allow the channels to stay open during slow depolarizations, thus amplifying pain signals.