Neonatal injury rapidly alters markers of pain and stress in rat pups

Abstract

Less than 60% of infants undergoing invasive procedures in the neonatal intensive care unit receive analgesic therapy. These infants show long-term decreases in pain sensitivity and cortisol reactivity. In rats, we have previously shown that inflammatory pain experienced on the day of birth significantly decreases adult somatosensory thresholds and responses to anxiety- and stress-provoking stimuli. These long-term changes in pain and stress responsiveness are accompanied by two-fold increases in central met-enkephalin and β-endorphin expression. However, the time course over which these changes in central opioid peptide expression occur, relative to the time of injury, are not known. The present studies were conducted to determine whether the observed changes in adult opioid peptide expression were present within the first postnatal week following injury. The impact of neonatal inflammation on plasma corticosterone, a marker for stress reactivity, was also determined. Brain, spinal cord, and trunk blood were harvested at 24 h, 48 h, and 7 d following intraplantar administration of the inflammatory agent carrageenan on the day of birth. Radioimmunoassay was used to determine plasma corticosterone and met-enkephalin and β-endorphin levels within the forebrain, cortex, midbrain, and spinal cord. Within 24 h of injury, met-enkephalin levels were significantly increased in the midbrain, but decreased in the spinal cord and cortex; forebrain β-endorphin levels were significantly increased as a result of early life pain. Corticosterone levels were also significantly increased. At 7 d post-injury, opioid peptides remained elevated relative to controls, suggesting a time point by which injury-induced changes become programmed and permanent.

Analgesia for Early-Life Pain Prevents Deficits in Adult Anxiety and Stress in Rats

“…Indeed, exposure of rat pups to morphine in the absence of pain increases opioid release in response to acute psychological stressors, reduces adult anxiety-related behaviors [59] , and decreases adult immobility in the FST and basal corticosterone levels [60] . Together, these findings support the hypothesis that early-life activation of the opioid system, either with injury-driven up-regulation in endogenous opioid peptides [20,25,58] or administration of morphine in the absence of pain, permanently reprograms circuits sensitive to anxiety and stress.…”

“…In turn, release of endogenous opioids, such as metenkephalin and β-endorphin, as well as neurohormones corticotropin-releasing factor, ACTH and corticosterone, are reduced [9,57,[68][69][70] . Aberrantly high levels of corticosterone and endogenous opioids during the early postnatal period, as we observed previously as a result of early-life pain [58] , are known to increase cell death [71] , decrease proliferation of neurons, glia and DNA synthesis [72] , decrease myelination [73] , disrupt axon outgrowth and synaptogenesis [74] , as well as decrease cortical thickness and hippocampal volume [75,76] , and increase the density of cortical GABAergic interneurons [75] . Together these findings suggest that unalleviated early-life pain may disrupt neural circuit formation.…”

“…Our working hypothesis is that morphine treatment for early-life pain experienced during a critical neurodevelopmental period (P0-P8 [18] ; comparable to a human preterm infant at 24-36 gestational weeks) mitigates the injury-induced increase in afferent nociceptive drive and reduces activation of supraspinal circuits subserving pain and stress [18,23,25,58,[63][64][65][66][67] . In turn, release of endogenous opioids, such as metenkephalin and β-endorphin, as well as neurohormones corticotropin-releasing factor, ACTH and corticosterone, are reduced [9,57,[68][69][70] .…”

“…This suggests that early activation of the opioid system, either endogenously by noxious stimulation [58] or exogenously with morphine, produces long-term changes in adult responses to anxiety-and stress-provoking stimuli. Indeed, exposure of rat pups to morphine in the absence of pain increases opioid release in response to acute psychological stressors, reduces adult anxiety-related behaviors [59] , and decreases adult immobility in the FST and basal corticosterone levels [60] .…”

Long-term changes in adaptive behavior of rats after inflammatory pain stimulation during neonatal development

“…However, the data of these studies are contradictive. There are reports on long-term hypalgesia as INTRODUCTION Fundamental and clinical investigations show that pain experienced during the neonatal period of development has long-term consequences [1][2][3][4][5]. A high sensitivity to pain stimulation during the neonatal period is determined by the peculiarities of nociception at early postnatal ontogenesis (a dominant role of low-threshold A-fibers in nociception, long-lasting reaction to pain, high density of receptive fields in the dorsal horns of the well as hyperalgesia in adult animals after inflammatory pain stimulation by peripheral injection of carrageen or Freund adjuvant during the neonatal period [8,9].…”