Deficits in glycinergic inhibition within adult spinal nociceptive circuits after neonatal tissue damage

Abstract

Tissue injury during a critical period of early postnatal development can alter pain sensitivity throughout life. However, the degree to which neonatal tissue damage exerts prolonged effects on synaptic signaling within adult spinal nociceptive circuits remains unknown. Here we provide evidence that a transient surgical injury of the hind paw during the neonatal period compromises inhibitory transmission within the adult mouse superficial dorsal horn (SDH), while the same incision occurring during the third week of life failed to evoke these long-term modifications of the SDH synaptic network. The decrease in phasic inhibitory signaling after early tissue damage reflected a selective reduction in glycine receptor (GlyR)-mediated input onto both GABAergic and presumed glutamatergic neurons within lamina II of the adult SDH. Meanwhile, neonatal incision significantly decreased the density of tonic GlyR-mediated current only in the presumed glutamatergic population during adulthood. These persistent changes in synaptic function following early injury occurred in the absence of significant alterations in the transcription of genes known to be important for glycinergic transmission. These findings suggest that aberrant sensory input during early life has permanent consequences for the functional organization of nociceptive synaptic circuits within the adult spinal cord.

Early life vincristine exposure evokes mechanical pain hypersensitivity in the developing rat

“…It should also be noted that aberrant sensory input resulting from injury during the early postnatal period can have prolonged consequences for central nociceptive processing, including (but not limited to) a disruption in the balance between excitatory and inhibitory synaptic transmission and a facilitation of synaptic long-term potentiation (LTP) in the spinal dorsal horn [40,41], elevated spinal neuroimmune responses [4,67], heightened opioidergic tone in the brain [34,35] and changes in descending inhibitory pathways [68,76]. This highlights the need for future studies examining the effects of early life VNC exposure on the functional organization of developing pain networks within the CNS.…”

“…This highlights the need for future studies examining the effects of early life VNC exposure on the functional organization of developing pain networks within the CNS. Similarly, while mounting evidence from both rodents [20,39–41,54,66,68,71] and humans [26,27,69] suggests that neonatal injuries can ‘prime’ developing nociceptive pathways such that a subsequent injury evokes an exacerbated level of pain hypersensitivity, it remains to be determined whether neonatal VNC treatment modulates the behavioral response to an unrelated injury later in life. Finally, while the present study investigated the effects of VNC administration to naïve rats as a means to isolate the effects of the drug itself, it will ultimately be critical to elucidate how neonatal VNC alters pain sensitivity and nociceptive circuitry when administered in the presence of ALL or other pediatric cancers, in order to better mimic the clinical scenario.…”

“…For example, neonatal tissue damage can evoke unique changes in nociceptive processing within both the peripheral [6,18,32] and central nervous systems [39–41,67]. In addition, the effects of peripheral nerve injury in the rodent are highly age-dependent [21,29,45], with the onset of neuropathic pain delayed in the neonate due to a significant developmental shift in spinal neuroimmune signaling towards a more pro-inflammatory phenotype during adolescence [4,43].…”

Neonatal Tissue Damage Promotes Spike Timing-Dependent Synaptic Long-Term Potentiation in Adult Spinal Projection Neurons

“…At postnatal day 3 (P3) or P21, female mice (FVB-Tg(GadGFP)4570Swn; The Jackson Laboratory) were anesthetized with isoflurane (2-3%) and a small incision was made through the skin and underlying muscle of the plantar hindpaw as described previously (Brennan et al, 1996;Li et al, 2013). The skin was immediately closed with 7-0 (at P3) or 5-0 (at P21) suture (Ethicon) and the wound fully healed in Յ 2 weeks.…”

Long-Term Consequences of Neonatal Injury

“…40 The same injury, when performed in the neonatal period, decreases inhibitory transmission through a reduction in the inhibitory glycinergic input onto the spinal dorsal horn neurons in the adult. 41 Therefore, the functional organization of adult nociceptive circuitry is permanently changed by surgical incision in the neonate. In addition to these changes in synaptic connectivity in the adult dorsal horn following neonatal injury, there is also a long-lasting dampening in the intrinsic firing properties of the spinal dorsal horn neurons.…”