Synaptic Function within Mature Central Pain Networks after Neonatal Injury

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Despite growing evidence that tissue damage during a critical period of early life can exacerbate pain severity following subsequent injury, the cellular and molecular mechanisms by which neonatal trauma can ‘prime’ developing nociceptive pathways remain unclear. Furthermore, while inhibitory interneurons in the adult spinal dorsal horn (DH) are known to be comprised of multiple subpopulations which regulate distinct aspects of sensory processing, the classes of inhibitory interneurons that are important for shaping pain sensitivity in the neonate have yet to be identified. Finally, the degree to which neonatal injury primes developing pain circuits by disrupting the maturation of specific subpopulations of inhibitory DH neurons necessary for feedforward inhibition of ascending spinal projection neurons has yet to be elucidated. The long-term goal is to facilitate the design of age-appropriate strategies to treat chronic pain by advancing our understanding of the developmental neurobiology of central nociceptive networks. The objective of this application is to elucidate the consequences of early tissue injury for the maturation of identified inhibitory synaptic circuits within the spinal DH. The central hypothesis is that neonatal tissue damage disrupts the development of primary afferent drive to dynorphin-expressing (DYN) interneurons mediating feedforward inhibition of ascending projection neurons, which contributes to the priming of spinal nociceptive circuits to subsequent injury. The rationale of the proposed research is that by yielding novel insight into the postnatal development of distinct spinal inhibitory circuits under normal and pathological conditions, these studies will lay a conceptual foundation for new therapeutic approaches to restrict the output of the spinal pain network in an age-specific manner and minimize the adverse long-term effects of neonatal injury on the developing CNS. 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) Determine how early tissue damage shapes primary afferent drive to inhibitory interneurons in the developing DH; (2) Identify the DH interneurons which mediate feedforward inhibition of developing spinal projection neurons under normal and pathological conditions; and (3) Identify the inhibitory interneurons in the developing DH whose ability to suppress pain is compromised by neonatal tissue injury. These aims will be accomplished by using a multidisciplinary experimental approach that includes in vitro electrophysiological, optogenetic, chemogenetic, behavioral and immunohistochemical techniques. The outcome of these investigations will be the first insight into how early tissue damage alters the functional organization of inhibitory microcircuits in the developing spinal nociceptive network and thereby diminishes their ability to suppress pain sensation. As a result, the proposed research is significant because it will identify the specific inhibitory synaptic pathways within the spinal DH that must ultimately be restored in order to prevent the exaggerated susceptibility to chronic pain following neonatal tissue damage.