Pain is a percept resulting from activity of the nociceptive system, a subdivision of the somatosensory system. Ion channels play a role throughout the nociceptive system. Peripheral sensory transduction involves TRPV1 and P2X3 receptor channels. Action potential generation and conduction are governed by several voltage-gated sodium and potassium channels, some of them specific to nociceptive neurons (e.g. NaV1.9, KV1.4). Pre- and postsynaptic receptors and channels are largely shared with other CNS synapses, with the possible exception of the G-protein-coupled substance P receptor NK1R. Experimental elimination of peripheral neurons that express TRPV1 or central neurons that express NK1R markedly reduces pain sensitivity. Congenital insensitivity to pain may result from a decrease in TRPV1 expressing neurons, as an indirect consequence of deficiencies in the nerve growth factor receptor trkA. However, there are no known channelopathies in nociceptive sensory transduction or synaptic transmission. TRP channelopathies affect the kidney and electrolyte balance instead. Channelopathies with a pain phenotype have been found for NaV1.7: gain of function mutations lead to erythromelalgia or to paroxysmal extreme pain disorder, whereas loss of function mutations lead to insensitivity to pain. NaV1.7 has slow kinetics and is not specific for nociceptive neurons. Gain of function mutations lead to a slow depolarization that reduces excitability via sodium channel inactivation except in neurons expressing NaV1.8. These human genetic data have raised interest in action potential generation in nociceptive nerve terminals. Subtype-selective sodium channel blockers are being evaluated as novel analgesics. References Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cell 139: 267-284 Greffrath W, Schwarz ST, Büsselberg D, Treede RD (2009) J Neurophysiol 102:424-36 Bhattacharya A, Wickenden AD, Chaplan SR (2009) Neurotherapeutics 6: 663-678