Long-term behavioral effects of repetitive pain in neonatal rat pups

Human preterm neonates are subjected to repetitive pain during neonatal int ensive care. We hypothesized that exposure to repetitive neonatal pain may cause permanent or long-term changes because of the developmental plasticit y of the immature brain. Neonatal rat pups were stimulated one, two, or fou r times each day from P0 to P7 with either needle prick (noxious groups N-1 , N-2, N-4) or cotton tip rub (tactile groups T-1, T-2, T-4) In groups N-2, N-4, T-2, T-4 stimuli were applied to separate paws at hourly intervals;ea ch paw was stimulated only once a day. Identical rearing occurred from P7 t o P22 days. Pain thresholds were measured on P16, P22, and P65 (hot-plate t est), and testing for defensive withdrawal, alcohol preference, air-puff st artle, and social discrimination tests occurred during adulthood. Adult rat s were exposed to a hot plate at 62 degrees C for 20 s, then sacrificed and perfused at 0 and 30 min after exposure. Fos expression in the somatosenso ry cortex was measured by immunocytochemistry. Weight gain in the N-2 group was greater than the T-2 group on P16 (p < 0.05) and P22 (p < 0.005); no d ifferences occurred in the other groups. Decreased pain latencies were note d in the N-4 group [5.0 +/- 1.0 s vs. 6.2 +/- 1.4 s on P16 (p < 0.05); 3.9 +/- 0.5 s vs. 5.5 +/- 1.6 s on P22 (p < 0.005)], indicating effects of repe titive neonatal pain on subsequent development of the pain system. As adult s, N-4 group rats showed an increased preference for alcohol (55 +/- 18% vs . 32 +/- 21%; p = 0.004); increased latency in exploratory and defensive wi thdrawal behavior (p < 0.05); and a prolonged chemosensory memory in the so cial discrimination test (p < 0.05). No significant differences occurred in corticosterone and ACTH levels following air-puff startle or in pain thres holds at P65 between N-4 and T-4 groups. Fos expression at 30 min after hot -plate exposure was significantly greater in all areas of the somatosensory cortex in the T-4 group compared with the N-4 group (p < 0.05), whereas no differences occurred just after exposure. These data suggest that repetiti ve pain in neonatal rat pups may lead to an altered development of the pain system associated with decreased pain thresholds during development. Incre ased plasticity of the neonatal brain may allow these and other changes in brain development to increase their vulnerability to stress disorders and a nxiety-mediated adult behavior. Similar behavioral changes have been observ ed during the later childhood of expreterm neonates who were exposed to pro longed periods of neonatal intensive care. (C) 1999 Elsevier Science Inc.