SODIUM CHANNELS AND EXCITABILITY OF VISCERAL AFFERENTS

University Of Maryland Baltimore, Baltimore MD

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Abstract

Pain resulting from injury and inflammation of hollow organs is one of the most common reasons people seek medical attention. Visceral pain is associated with the sensitization of primary afferent neurons innervating inflamed; i.e., those arising from thoracolumbar and lumbosacral dorsal root ganglion (DRG). Visceral pain is often difficult to treat possibly reflecting the unique properties of visceral afferents and/or the unique structures these afferents innervate. Nevertheless, our present understanding of the neurobiology of sensory neurons and their response to injury is derived largely from studies on somatic afferents. Recent observations that have profound implications for the care and treatment of babies born pre-naturally, particularly those requiring serious medical interventions, suggest that there is a window of vulnerability within which developing neuronal circuitry underlying nociception may be permanently alerted by noxious inflammatory stimuli. The nature and extent of these changes have yet to be investigated in detail, however, available evidence suggests that changes in primary afferent neurons innervating neonatally inflamed tissue contribute to alterations in nociceptive processing. The experiments described in proposal are designed to test four specific hypotheses concerning the role of primary afferents in general and Na+ channels in particular in changes in nociceptive processing occur in response to persistent inflammation and/or following neonatal inflammation. First, that inflammation-induced changes in the processing of visceral stimuli reflect differences between afferents in the hypogastric/lumbar colonic nerve and the pelvic nerve. Second, that differences in the excitability of hypogastric/lumbar colonic, pelvic and somatic nerve afferents reflect differences in the biophysical properties and/or pattern of expression of VG Na+ channels within these afferent populations. And fourth, that changes in nociceptive processing observed in adults exposed to a noxious stimulus as neonates reflect changes in biophysical properties and/or pattern of expression of VG Na+ channels within these afferent populations. We will test these hypotheses in experiments described under 4 Specific Aims that involve single unit electrophysiological recording in vivo, patch-clamp electrophysiological recording in vitro, RT-PCR and behavioral assays employing a method to selectively decrease the amount of targeted protein in specific neuronal populations.