Aberrant Synaptic Integration in Adult Lamina I Projection Neurons Following Neonatal Tissue Damage

Abstract

Mounting evidence suggests that neonatal tissue damage evokes alterations in spinal pain reflexes which persist into adulthood. However, less is known about potential concomitant effects on the transmission of nociceptive information to the brain, as the degree to which early injury modulates synaptic integration and membrane excitability in mature spinal projection neurons remains unclear. Here we demonstrate that neonatal surgical injury leads to a significant shift in the balance between synaptic excitation and inhibition onto identified lamina I projection neurons of the adult mouse spinal cord. The strength of direct primary afferent input to mature spinoparabrachial neurons was enhanced following neonatal tissue damage, whereas the efficacy of both GABAergic and glycinergic inhibition onto the same population was compromised. This was accompanied by reorganization in the pattern of sensory input to adult projection neurons, which included a greater prevalence of monosynaptic input from low-threshold A-fibers when preceded by early tissue damage. In addition, neonatal incision resulted in greater primary afferent-evoked action potential discharge in mature projection neurons.Overall, these results demonstrate that tissue damage during early life causes a long-term increase in the gain of spinal nociceptive circuits, and suggest that the prolonged consequences of neonatal trauma may not be restricted to the spinal cord but rather include excessive ascending signaling to supraspinal pain centers.

A “Wear and Tear” Hypothesis to Explain Sudden Infant Death Syndrome

“…The significantly increased risk of death or neurodevelopmental impairment in very low birth weight newborns following major or minor surgery that does not require a general anesthetic (52) is consistent with nociceptive exposure, pain, and overall neurotoxic risk (47, 53, 54). The American Academy of Pediatrics (AAP) and the Canadian Pediatric Society (CPS) have recognized the neurotoxic risk of pain in their joint policy statement urging the avoidance, prevention, and possible elimination of pain even during routine minor procedures to protect the developing brain (55).…”

“…The abnormal development of sensory pathways in the developing nervous system elicited by the pain during critical postnatal periods is manifested in later life following nociceptive reexposure by abnormal sensory thresholds and pain responses that are not restricted to the original site of postnatal trauma (74–76). Neonatal nociceptive exposure induces long-term hypoalgesia or hyperalgesia depending on the nature and timing of the trauma (54, 77) and is consistent with surgery and pain adversely impacting neurodevelopment independent of anesthetic (76). …”

Exposure to early life pain: long term consequences and contributing mechanisms

“…However, ß-endorphin and enkephalin mRNA and protein levels remain significantly elevated within the PAG into adulthood [43], indicating that early life pain permanently reprograms opioidergic circuits that are critical for pain management. Enhanced descending inhibition from the RVM [49] and increased excitability within the spinal cord dorsal horn [50-52] have also been reported in adult animals that experienced early life pain (see review:[53]). This blunted adult pain sensitivity is mediated by endogenous opioids, as systemic or intra-PAG administration of μ- or δ-opioid receptor antagonists attenuates the hypoalgesia [54].…”

“…This change in intrinsic spinal cord signaling is thought to prime developing pathways and enhance future responses to subsequent tissue damage [41,55]. Lamina I projection neurons also show increased excitatory postsynaptic current (EPSC) amplitudes in neonatally injured adults, as well as increased afferent input from low threshold myelinated Aδ (nociceptive) fibers, and decreased GABA A and glycine receptor contributions to inhibitory postsynaptic currents (IPSCs) [52]. Altered excitation and inhibition of adult lamina II neurons has also been reported [51].…”

Translational studies identify long-term impact of prior neonatal pain experience

“…[6-8; 208] In adult mice with prior hindpaw incision on postnatal day 3 (P3), excitatory afferent input to lamina I projection neurons is enhanced while the efficacy of GABergic and glycinergic inhibition is reduced. [110] In addition, prior neonatal incision alters the temporal requirements for long-term potentiation at primary afferent synapses onto adult lamina I projection neurons, unmasks a role of calcium-permeable AMPA receptors, and thus predisposes to enhanced response to subsequent injury. [108] Prolonged afferent blockade prior to neonatal incision (bupivacaine hydrochloride powder or tetrodotoxin microcapillaries implanted adjacent to sciatic nerve) prevented the increase in glutamatergic miniature excitatory postsynaptic currents (mEPSCs) following incision at P3 but not older ages, [111] again highlighting the vulnerability of neonatal spinal nociceptive circuits to activitydependent change.…”