Knockdown of sodium channel Na(V)1.6 blocks mechanical pain and abnormal bursting activity of afferent neurons in inflamed sensory ganglia

Inflammatory processes in the sensory ganglia contribute to many forms of chronic pain. We previously showed that local inflammation of the lumbar sensory ganglia rapidly leads to prolonged mechanical pain behaviors and high levels of spontaneous bursting activity in myelinated cells. Abnormal spontaneous activity of sensory neurons occurs early in many preclinical pain models and initiates many other pathological changes, but its molecular basis is not well understood. The sodium channel isoform Na(V)1.6 can underlie repetitive firing and excitatory persistent and resurgent currents. We used in vivo knockdown of this channel via local injection of siRNA to examine its role in chronic pain after local inflammation of the rat lumbar sensory ganglia. In normal dorsal root ganglion (DRG), quantitative polymerase chain reaction showed that cells capable of firing repetitively had significantly higher relative expression of Na(V)1.6. In inflamed DRG, spontaneously active bursting cells expressed high levels of Na(V)1.6 immunoreactivity. In vivo knockdown of Na(V)1.6 locally in the lumbar DRG at the time of DRG inflammation completely blocked development of pain behaviors and abnormal spontaneous activity, while having only minor effects on unmyelinated C cells. Current research on isoform-specific sodium channel blockers for chronic pain is largely focused on Na(V)1.8 because it is present primarily in unmyelinated C fiber nociceptors, or on Na(V)1.7 because lack of this channel causes congenital indifference to pain. However, the results suggest that Na(V)1.6 may be a useful therapeutic target for chronic pain and that some pain conditions may be mediated primarily by myelinated A fiber sensory neurons. (C) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.