Developmental Regulation of Intrinsic Excitability in Spinal Pain Networks

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DESCRIPTION (provided by applicant): Although it is clear that even the youngest infants can experience significant pain as the result of injury, disease, surgery or intensive care therapy, little is known about how tissue damage affects the intrinsic excitability of neurons within developing pain circuits in the central nervous system (CNS). Since the superficial dorsal horn of the spinal cord (SDH) functions as a critical relay station in the pain pathway, a better understanding of how the intrinsic membrane properties of SDH neurons are influenced by tissue injury at different ages represents an important and logical first step towards addressing this issue. The long-term goal is to improve the clinical treatment of pain in infants and children by identifying novel analgesic strategies which are more developmentally appropriate. The overall objective of this application, which is the next step in pursuit of that goal, is to identify the key ionic conductances which regulate the intrinsic excitability of developing neurons within the SDH under normal and pathological conditions. The central hypothesis is that excitatory interneurons within lamina I exhibit intrinsic, pacemaker-type oscillations during a critical period of early postnatal development, which are driven by persistent Na+ and Ca2+ currents and facilitated by neonatal tissue damage. The rationale of the proposed research is that understanding how intrinsic neuronal excitability is specifically regulated within immature nociceptive circuits will reveal new ways to modulate their output which would not be evident from studies in the adult. Guided by strong preliminary data, the central hypothesis will be tested and the overall objective of this application achieved by pursuing the following specific aims: 1) Identify the SDH neurons which are spontaneously active during early postnatal development; (2) Elucidate the ionic mechanisms which drive the intrinsic firing of neonatal SDH neurons; and (3) Detect cell-type-specific changes in ion channel expression and intrinsic excitability within the developing SDH network following early tissue damage. These aims will be accomplished by using in vitro electrophysiological, immunohistochemical and biochemical techniques to characterize the ionic mechanisms regulating neuronal excitability in identified subtypes of developing SDH neurons and determine the extent to which these intrinsic membrane properties are modulated by tissue injury in an age-dependent manner. The outcome of these investigations will be new insight into how activity within immature spinal pain networks is controlled at the cellular level. As a result, the proposed research is significant because it will begin to provide the knowledge needed to develop evidence- based treatments for chronic pediatric pain. PUBLIC HEALTH RELEVANCE: The expected outcomes of the proposed research will have a positive impact on public health by illustrating that the underlying causes of pain hypersensitivity under pathological conditions are highly developmentally regulated. By elucidating the mechanisms by which early tissue damage modulates intrinsic neuronal excitability within central nociceptive networks during postnatal development, this research also brings the promise of identifying novel approaches to regulate pain pathways in an age-specific manner, which would greatly aid efforts to improve the clinical management of pediatric pain.