Rewiring of Developing Spinal Nociceptive Circuits by Neonatal Injury and Its Implications for Pediatric Chronic Pain

Abstract

Significant evidence now suggests that neonatal tissue damage can evoke long-lasting changes in pain sensitivity, but the underlying cellular and molecular mechanisms remain unclear. This review highlights recent advances in our understanding of how injuries during a critical period of early life modulate the functional organization of synaptic networks in the superficial dorsal horn (SDH) of the spinal cord in a manner that favors the excessive amplification of ascending nociceptive signaling to the brain, which likely contributes to the generation and/or maintenance of pediatric chronic pain. These persistent alterations in synaptic function within the SDH may also contribute to the well-documented "priming" of developing pain pathways by neonatal tissue injury.

Keywords: GABA; dorsal horn; glutamate; glycine; incision; neonate; pain; rodent; spinal cord; synapse.

Figure 1

Early tissue damage widens the timing window for evoking spike timing-dependent long-term potentiation (t-LTP) at sensory synapses onto adult spinal projection neurons. Left column (Naïve): In naïve adult mice, highly correlated presynaptic (black) and postsynaptic (red) action potential firing (i.e., occurring within a window of 10–20 ms; green box) led to a strengthening of primary afferent synapses onto ascending lamina I projection neurons. This reflected an increase in the probability of glutamate release from the presynaptic terminals of the sensory neurons, as illustrated here by a larger size of the presynaptic terminals (black triangles in bottom panels). Right column (Neonatal Incision): In adult mice subjected to neonatal surgical injury, the timing window for generating t-LTP (green box) at afferent synapses onto spinal projection neurons significantly widened, such that poorly correlated presynaptic and postsynaptic firing (at pairing intervals ≥50 ms; middle panel) was still able to generate t-LTP. This enhanced propensity to generate t-LTP likely results, at least in part, from an elevated expression of Ca²⁺-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) (blue rectangles) in mature projection neurons following early tissue damage, since blocking these glutamate receptors prevented t-LTP in neonatally-injured mice but not naïve littermate controls [69]. NMDA: N-methyl-D-aspartate.