Abstract
BackgroundThe importance of neonatal experience upon behaviour in later life is increasingly recognised. The overlap between pain and reward pathways led us to hypothesise that neonatal pain experience influences reward-related pathways and behaviours in adulthood.Methodology/Principal FindingsRat pups received repeat plantar skin incisions (neonatal IN) or control procedures (neonatal anesthesia only, AN) at postnatal days (P)3, 10 and 17. When adult, rats with neonatal ‘pain history’ showed greater sensory sensitivity than control rats following acute plantar skin incision. Motivational behaviour in the two groups of rats was tested in a novelty-induced hypophagia (NIH) paradigm. The sensitivity of this paradigm to pain-induced changes in motivational behaviour was shown by significant increases in the time spent in the central zone of the arena (43.7±5.9% vs. 22.5±6.7%, p<0.05), close to centrally placed food treats, and decreased number of rears (9.5±1.4 vs. 19.2±2.3, p<0.001) in rats with acute plantar skin incision compared to naive, uninjured animals. Rats with a neonatal ‘pain history’ showed the same pain-induced behaviour in the novelty-induced hypophagia paradigm as controls. However, differences were observed in reward-related neural activity between the two groups. Two hours after behavioural testing, brains were harvested and neuronal activity mapped using c-Fos expression in lateral hypothalamic orexin neurons, part of a specific reward seeking pathway. Pain-induced activity in orexin neurons of control rats (18.4±2.8%) was the same as in uninjured naive animals (15.5±2.6%), but in those rats with a ‘pain history’, orexinergic activity was significantly increased (27.2±4.1%, p<0.01). Furthermore the extent of orexin neuron activation in individual rats with a ‘pain history’ was highly correlated with their motivational behaviour (r = −0.86, p = 0.01).Conclusions/SignificanceThese results show that acute pain alters motivational behaviour and that neonatal pain experience causes long-term changes in brain motivational orexinergic pathways, known to modulate mesolimbic dopaminergic reward circuitry.
Highlights
Studies on the long-term impact of early-life experience upon the developing nervous system have shown that infant experience, including pain, can have profound effects on adult neural processing [1,2,3,4,5,6,7,8,9,10,11,12]
Conclusions/Significance: These results show that acute pain alters motivational behaviour and that neonatal pain experience causes long-term changes in brain motivational orexinergic pathways, known to modulate mesolimbic dopaminergic reward circuitry
Baseline flexion withdrawal thresholds to mechanical stimulation of the plantar hindpaw were tested in two groups of adult animals - those that had received a repeated plantar skin incision as neonates (IN, n = 5), and controls that were anesthetized as neonates (AN, n = 5)
Summary
Studies on the long-term impact of early-life experience upon the developing nervous system have shown that infant experience, including pain, can have profound effects on adult neural processing [1,2,3,4,5,6,7,8,9,10,11,12]. At the spinal cord level, the neurobiological mechanisms associated with or driving the long-term effects of early pain include alterations in spinal nociceptive processing [18,24,25], shifts in nociceptive withdrawal reflexes [26,27,28] driven by activitydependent changes in primary afferent nerves and dorsal horn circuits [5,29,30], and altered gene expression [7] This has led to the concept of a ‘critical period’ for nociceptive development, during which noxious input can shape and define nociceptive behaviour for life [28,31]. The overlap between pain and reward pathways led us to hypothesise that neonatal pain experience influences reward-related pathways and behaviours in adulthood
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