Although tissue damage commonly occurs during neonatal intensive care treatment and can alter pain sensitivity throughout life, whether such early injuries can evoke long-term changes in synaptic function within mature nociceptive pathways remains unknown. As a result, the cellular and molecular mechanisms which contribute to the persistent alterations in pain sensitivity following neonatal injury are still unclear. The long- term goal is to improve the clinical treatment of pain by determining how neonatal tissue injury influences nociceptive processing throughout development. The overall objective of this application is to identify changes within the mature rodent superficial dorsal horn (SDH) network following early tissue damage that facilitate activity-dependent plasticity at nociceptive synapses onto ascending projection neurons, which constitute the output of the spinal pain network. The central hypothesis is that neonatal tissue damage evokes persistent deficits in the function of spinal inhibitory circuits which result in decreased feed-forward inhibition of adult lamina I projection neurons, leading to an enhancement of long-term potentiation (LTP) at nociceptive synapses onto these cells. The rationale of the proposed research is that by elucidating how early tissue damage modulates the future plasticity of synapses onto adult projection neurons, these experiments will reveal potential mechanisms by which developing spinal pain circuits can be """"""""primed"""""""" to produce a greater degree of hyperexcitability following injuries at later ages. 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 prolonged effects of neonatal tissue injury on the efficacy of GABAergic and glycinergic signaling onto mature lamina I projection neurons;(2) Elucidate how early tissue damage modulates the integration of sensory input within spinal lamina I projection neurons during adulthood;and (3) Determine the extent to which neonatal injury alters synaptic plasticity in mature spinal projection neurons.
These aims will be accomplished by using in vitro electrophysiological, immunohistochemical, and tract-tracing techniques to characterize the effects of neonatal tissue damage on synaptic signaling within the adult SDH and determine the overall consequences of early injury for signal processing within ascending projection neurons. The outcome of these investigations will be the identification of permanent alterations in the synaptic organization of spinal pain networks following early tissue damage which promote the amplification of ascending pain signals in the CNS following subsequent noxious stimulation. As a result, the proposed research is significant because it will enhance our understanding of how nociceptive synaptic plasticity in central pain pathways is modulated by painful experience during the neonatal period and thus provide mechanistic insight into the emerging link between pediatric and adult chronic pain conditions.
The expected outcomes of the proposed research will have a positive impact on public health by illustrating that the organization of pain pathways in the adul is highly influenced by sensory experience during the neonatal period. By identifying the persistent effects of neonatal tissue damage on synaptic function within developing nociceptive circuits, this research will provide mechanistic insight into the emerging link between pediatric and adult chronic pain conditions and also brings the promise of designing novel interventional strategies to limit the long-term consequences of neonatal injury for pain sensitivity.
|Baccei, Mark L (2016) Rewiring of Developing Spinal Nociceptive Circuits by Neonatal Injury and Its Implications for Pediatric Chronic Pain. Children (Basel) 3:|
|Walker, Suellen M; Beggs, Simon; Baccei, Mark L (2016) Persistent changes in peripheral and spinal nociceptive processing after early tissue injury. Exp Neurol 275 Pt 2:253-60|
|Li, Jie; Baccei, Mark L (2016) Neonatal Tissue Damage Promotes Spike Timing-Dependent Synaptic Long-Term Potentiation in Adult Spinal Projection Neurons. J Neurosci 36:5405-16|
|Li, Jie; Kritzer, Elizabeth; Craig, Paige E et al. (2015) Aberrant synaptic integration in adult lamina I projection neurons following neonatal tissue damage. J Neurosci 35:2438-51|