Polymorphisms in ion channel genes: emerging roles in pain

Why does one soldier, after sustaining a missile wound in the radial nerve on the battlefield, experience incapacitating neuropathic pain, while another, with a similar injury, complains of motor and sensory deficits in the absence of pain? Why is one patient with diabetic neuropathy disabled with neuropathic pain, while another patient with diabetic neuropathy of apparently similar severity experiences numbness or paraesthesias that are not painful? Pain is a complex phenomenon, mediated by transductive processes in the periphery, conduction to the spinal cord via first-order spinal sensory (dorsal root ganglion) neurons and processing at multiple higher levels that include the dorsal horn, thalamus and cortex. Multiple processes and molecules undoubtedly shape the perception of pain. Exciting progress, however, has recently been made in linking common variants of genes encoding two different ion channels within first-order sensory neurons along the pain pathway to inter-individual differences in pain. Discovery and characterization of these genetic variants, and of additional variants that will likely be identified in the future, open up the possibility of understanding more fully, at the molecular level, the processes that shape pain, and which may point the way to new therapeutic strategies.Ion channels play major roles in electrical signalling along the pain pathway; their central role in this process is underscored by the preferential expression within dorsal root ganglion neurons of three sodium channels, Nav1.7, Nav1.8 and Nav1.9, that are not expressed at high levels within the CNS (Cummins et al. , 2007). It is now well established that mutations of two ion channel genes can produce pain syndromes.The Nav1.7 sodium channel, which is preferentially expressed within dorsal root ganglion neurons including nocioceptors and sympathetic ganglion neurons (Djouhri et al. , 2003), displays slow inactivation in the closed-state near resting …