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.
Highlights
Pain processing in the central nervous system (CNS) begins in the dorsal horn of the spinal cord which receives direct input from peripheral sensory neurons that are activated by noxious stimuli, defined as stimuli that damage or threaten to damage normal tissue
Nociceptive information is conveyed to the brain by an exclusive group of projection neurons concentrated mainly in laminae I and V [1], whose firing is strongly controlled by the balance of activity in the different excitatory and inhibitory (expressing gamma-aminobutyric acid (GABA) and/or glycine) populations of interneurons
Recent evidence suggests that inhibitory interneurons expressing parvalbumin or dynorphin may tonically suppress the activation of ascending projection neurons by innocuous mechanical stimuli, and pharmacogenetic silencing of these interneurons evokes mechanical pain hypersensitivity including allodynia [8,9]
Summary
Pain processing in the central nervous system (CNS) begins in the dorsal horn of the spinal cord which receives direct input from peripheral sensory neurons that are activated by noxious stimuli, defined as stimuli that damage or threaten to damage normal tissue These signals are integrated with other types of incoming sensory information, including touch, before being transmitted to nociceptive circuits in the brain where the perception of pain emerges. Peripheral inflammation or surgical incision of the rodent hindpaw during the first days of life leads to a transient elevation in glutamate release within the superficial dorsal horn (SDH) that is not observed following the same injury at later ages [29] This enhanced glutamate release includes a strengthening of high-threshold (i.e., putative nociceptive) primary afferent synapses onto lamina II interneurons that requires nerve growth factor (NGF) activation of tropomyosin receptor kinase A (trkA) receptors [30]. This is interesting in light of behavioral studies showing a delayed onset of neuropathic pain after peripheral nerve injury during early life [33,34]
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