Problem statement: Exposure to pain and injury in early-life (early-life pain, ELP) is associated with altered pain behaviour in adults. However, it is not known whether ELP has any effect upon adult cortical pain networks or upon functional connectivity between the key cortical regions involved in the sensory and emotional dimensions of pain.  Here we recorded pain related neural activity in the adult rat somatosensory cortex (S1, sensory-discriminative) and the medial prefrontal cortex (mPFC, associative-affective) in a model of early-life pain.  We hypothesized that early-life pain experiences in critical periods alter adult functional pain connectivity in the rat S1 and mPFC.
Methods: Ongoing wireless electrophysiological recording at S1 and mPFC was performed in two groups of awake adult male Sprague-Dawley rats before and up to 10 days after the hindpaw skin incision. One group had received the same skin incision in the first week of life (II, n=8) and the other did not (NI, n=8). The same recordings were conducted in a control group of animals which did not receive any incision (NN, n =8). Pain sensitivity (Paw withdraw threshold, PWT) was also measured using electronic von Frey stimulation on the hindpaw while recording local field potentials in S1 and mPFC. 
Results: Rats who had a neonatal skin incision (II) had a lower paw withdrawal threshold to mechanical stimulation following adult skin injury compared to NI (GLM; type III χ2(2) =349.86, p < 0.0001). This increase in hypersensitivity was directly correlated with an increase in sensory evoked (von Frey stimulation) delta and gamma energy in S1 and delta-gamma frequency coupling in the same cortical area, which were more pronounced in II than NI rats. In addition, skin injury elicited an increase in S1-mPFC connectivity which was significantly prolonged in II rats, extending for 4 days post injury (1 way ANOVA, Day of incision: F(2, 28) = 11.75, p= 0.0002; 4 days following incision: F (2, 28) = 3.84, p=0.03) and also correlated to behavioural pain hypersensitivity.  
Conclusion: Painful sensory experiences in early life have a significant effect on both behavioural pain sensitivity and the functional connectivity of pain-related cortical circuits.  Our study elucidates an important link between persistent hypersensitivity and both local and long-range neural circuit alteration following hind-paw skin injury in adult rats, underlying the impact of early-life pain experience. The results provide novel insights into the role of S1 and mPFC in the regulation of pain sensation and affective pain.