Neuro-glia and the delayed onset of pain-like hypersensitivity following infant nerve injury

Peripheral nerve injuries in adults can trigger neuropathic pain which coincides with alterations in dorsal horn neuronal activity and glial cells residing in the dorsal horn, and infiltrating T-lymphocytes. These cells synthesise and release pro-inflammatory mediators that can directly and indirectly sensitize dorsal horn neurones and contribute to neuropathic pain. Neuropathic pain is rare in infants and studies presented in this thesis show that a spared nerve injury (SNI) at postnatal day (P) 10 does not result in pain-like behaviour but triggers an anti-inflammatory immune response in the dorsal horn, not observed in nerve injured adults. However, if infant SNI treated animals are intrathecally administered with the pro-inflammatory mediator tumor necrosis factor (TNF) or lipopolysaccharide-activated microglia they develop pain-like behaviour while blockade of anti-inflammatory activity after infant SNI 'unmasks' neuropathic pain-like behaviour. Thus, nerve injury induced pain-like hypersensitivity in infants is actively suppressed by dominant anti-inflammatory neuro-immune activity. The anti-inflammatory response can also be evoked by direct C-fibre nerve stimulation in the infant, but not in adult rodents. However, mechanical hypersensitivity does eventually develop following early life nerve injury in the rat at adolescence (Vega-Avelaira et al., 2012). Longitudinal studies presented in this thesis indicate that hypersensitivity emerges in response to not only mechanical stimulation but also following innocuous and noxious cold stimulation of the hind paw, and contralateral weight bearing. The emergence of behavioural hypersensitivity at adolescence coincides with an increase in spontaneous and evoked- activity of wide dynamic dorsal horn neurons, that is absent in sham controls. In addition, the immune response in the dorsal horn switches from an anti-inflammatory response to pro-inflammatory, characterised by an increase in the expression of TNF and Brain-derived neurotrophic factor. This explains why neuropathic pain is rare in infants, but complex regional pain syndromes can emerge, for no observable reason at adolescence.