Background: The effect of neonatal anesthesia and pain on the developing brain is of considerable clinical importance but few studies have evaluated noxious surgical input to the infant brain under anesthesia. Here we tested the effect of increasing isoflurane concentration upon spontaneous and evoked nociceptive activity in the somatosensory cortex of rats at different postnatal ages. Methods: Intracortical extracellular field potentials evoked by hindpaw C-fiber electrical stimulation were recorded in the rat somatosensory cortex at postnatal day (P)7, 14, 21 and 30 during isoflurane anesthesia (n=7 per group). The amplitudes of evoked potentials and the energies of evoked oscillations (1-100Hz over 3 sec) were measured following equilibration at 1.5% isoflurane and during step increases in inspired isoflurane. Responses during and after plantar hindpaw incision were compared at P7 and P30 (n=6 per group). Results: At P7, cortical activity was silent at isoflurane 1.5% but noxious evoked potentials decreased only gradually in amplitude and energy with step increases in isoflurane. The resistance of noxious evoked potentials to isoflurane at P7 was significantly enhanced following surgical hindpaw incision (69±16% vs 6±1% in non-incised animals at maximum inspired isoflurane). This resistance was age dependent; at P14-30, noxious evoked responses decreased sharply with increasing isoflurane (step 3 (4%) P7: 50±9%, P30: 4±1% of baseline). Hindpaw incision at P30 sensitized noxious evoked potentials, but this was suppressed by higher isoflurane concentrations. Conclusions: Despite suppression of spontaneous activity, cortical evoked potentials are more resistant to isoflurane in young rats and are further sensitized by surgical injury.