Low back pain is a common problem with high morbidity costs to society, and many patients receive little relief from current therapies. Abnormal spontaneous activity of sensory neurons plays a key role in establishing the chronic pain state in a preclinical model relevant to low back pain, in which pain behaviors are induced by locally inflaming the lumbar dorsal root ganglion (DRG). This activity depends on a particular sodium channel isoform, Nav1.6, which can mediate persistent and resurgent sodium currents that in turn can underlie high- frequency/bursting activity. To date this channel has been largely ignored as a therapeutic target; however, knocking down this channel in the DRG in vivo with small interfering RNA can completely block development of pain behaviors induced by local DRG inflammation, without affecting behavior in the normal animal or motor function. Molecules involved in the inflammation process, such as cytokines/chemokines, have direct effects on sensory neuron excitability and pain. However, the underlying mechanisms are largely unexplored. We hypothesize that local inflammation of the DRG increases expression/release of inflammatory cytokines and enhances high-frequency/bursting discharges by regulating Nav1.6 in a subset of sensory neurons and leads to pain and hypersensitivity. The hypothesis will be tested in 3 Specific Aims: 1) Characterize functional and properties and anatomical distributions of Nav1.6 sodium channel in normal and inflamed sensory ganglia, testing the hypothesis that this channel plays a crucial role in abnormal spontaneous activity by mediating persistent and resurgent currents. Immunostaining methods will be used to test the hypothesis that bursting cells in inflamed ganglia are enriched in Nav1.6+ neurons and in molecules previously linked to pain, such as neuropeptide Y and CGRP. 2) Determine how pro-inflammatory cytokines regulate functional properties of Nav1.6 and Nav1.6-mediated spontaneous activity. We hypothesize that GRO/KC, a chemokine that is up- regulated in several pain models and in human patients with wide-spread pain syndromes, acts to increase spontaneous activity by regulating Nav1.6. 3) Assess the role of Nav1.6 in pathological pain. We will use novel behavioral assessment methods combined with local siRNA knockdown, and selective pharmacological block to determine whether this channel plays a role in the development and persistence of pain after DRG inflammation. Additionally, it will be tested in another back pain model and in a model of neuropathic pain.
These aims will be carried out using combined electrophysiological, behavioral, microscopy, and molecular methods. In particular, our laboratory's newly established techniques of manipulating the sensory ganglia in vivo with drugs or small interfering RNAs, in a highly localized fashion, combined with behavioral measurements and electrophysiology, provide a powerful integrated approach to understanding chronic pain mechanisms. Because inflammatory processes play a role in many types of chronic pain, the findings will be relevant not only to understanding low back pain, but other types of pain as well.
Chronic pain conditions are common, long-lasting, and debilitating. We propose to study the newly recognized role of inflammation and Nav1.6 sodium channel isoform in chronic pain. Using a rat model, we will determine how Nav1.6 and GRO/KC (known as interlukin-8 in human) directly affects the neurons that sense pain.
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