The postnatal reorganization of primary afferent input and dorsal horn cell receptive fields in the rat spinal cord is an activity‐dependent process

Abstract

The dorsal horn of the spinal cord in the newborn rat is characterized by large cutaneous mechanoreceptive fields, a predominance of A-fibre synaptic inputs and diffuse primary afferent A-fibre projections, all of which are gradually reduced and refined over the first postnatal weeks. This may be partly responsible for the reduction in cutaneous flexion reflex sensitivity of rats over the postnatal period. Here we show that chronic, local exposure of the dorsal horn of the lumbar spinal cord to the NMDA antagonist MK801 from birth prevents the normal functional and structural reorganization of A-fibre connections. Dorsal horn cells in spinal MK801-treated animals, investigated at eight weeks of age by in vivo electrophysiological recording, had significantly larger cutaneous mechanoreceptive fields and greater A-fibre evoked responses than vehicle controls. C-fibre evoked responses were unaffected. Chronic MK801 also prevented the normal structural reorganization of A-fibre terminals in the spinal cord. The postnatal withdrawal of superficially projecting A-fibre primary afferents to deeper laminae did not occur in treated animals although C-fibre afferent terminals and cell density in the dorsal horn were apparently unaffected. Spinal MK801-treated animals also had significantly reduced behavioural reflex thresholds to mechanical stimulation of the hindpaw compared to naïve and vehicle-treated animals, whereas noxious heat thresholds remained unaffected. The results indicate that the normal postnatal structural and functional development of A-fibre sensory connectivity within the spinal cord is an activity-dependent process requiring NMDA receptor activation.

Neuropathic Pain Is Constitutively Suppressed in Early Life by Anti-Inflammatory Neuroimmune Regulation

“…LPS is a bacterial endotoxin that activates Toll-like receptor 4 and subsequently MAPK and NF-B signaling pathways in microglia involved in the release of proinflammatory cytokines TNF␣ and IL-6 that also efficiently downregulate IL-10 (Harry, 2013). LPS-activated microglia release TNF at lower concentrations than the single TNF injection administered here (Welser-Alves and Milner, 2013;Berta et al, 2014); these lower levels of TNF sensitized young SNI mice, while leaving sham animals of the same age unaffected. However, despite being able to respond to stressors such as TNF or LPS-activated microglia, infant mice do not normally produce TNF and BDNF following infant nerve injury, due to an anti-inflammatory response.…”

“…The predominant anti-inflammatory response during the postnatal period may prevent excessive responses to microbes following the transition from the sterile environment in utero (Maynard et al, 2012) and facilitate microglial "synaptic stripping," removing damaged cells and dysfunctional synapses during development (Kettenmann et al, 2013). In other words, the antiinflammatory response to nerve damage in infants may be the indirect consequence of the requirements for normal postnatal development in the dorsal horn (Beggs et al, 2002;Bremner and Fitzgerald, 2008;Koch et al, 2012).…”

Developmental regulation of membrane excitability in rat spinal lamina I projection neurons

“…Previous studies have demonstrated that low-threshold A␤-fiber input to the SDH is more pronounced during the neonatal period (Beggs et al 2002;Daniele and MacDermott 2009;Jennings and Fitzgerald 1996) and becomes subject to tight inhibitory control at later ages (Torsney and MacDermott 2006). However, since primary afferents may target subtypes of SDH neurons in a highly selective manner Perl 2003, 2005;Zheng et al 2010), it remains to be determined whether newborn spinal projection neurons do in fact receive enhanced low-threshold sensory input.…”

Evidence for a Critical Period in the Development of Excitability and Potassium Currents in Mouse Lumbar Superficial Dorsal Horn Neurons

“…Electrophysiological studies have also confirmed that extensive reorganization of synaptic connections occurs in the SDH during development. The combined effect of this reorganization is to refine peripheral receptive field size, increase mechanical thresholds, and alter the contribution of large-fiber inputs (Beggs et al 2002;Jennings and Fitzgerald 1998;Park et al 1999;Torsney and Fitzgerald 2002).…”