Modelling the prolonged effects of neonatal pain

Alvares, Debie; Torsney, Carole; Beland, B; Reynolds, M. L.; Fitzgerald, Maria

doi:10.1016/s0079-6123(00)29028-6

Cited by 52 publications

(22 citation statements)

References 36 publications

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“…These data are the first mechanistic demonstration that early-life inflammatory pain changes adult responses to stress through alterations in the endogenous opioid system. Moreover, these data contribute to the growing number of animal studies addressing issues surrounding early-life pain, analgesia and anesthesia and their long-term consequences [19,42,43,44,45,46]. …”

Section: Discussionmentioning

confidence: 99%

A Single Neonatal Injury Induces Life-Long Deficits in Response to Stress

Victoria

Inoue²,

Young³

et al. 2013

Dev Neurosci

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Approximately 500,000 infants are born prematurely each year in the United States. These infants typically require an extensive stay in the neonatal intensive care unit (NICU), where they experience on average 14 painful and invasive procedures each day. These procedures, including repeated heel lance, insertion of intravenous lines, and respiratory and gastric suctioning, typically result in an inflammatory response, inducing pain and stress in the newborn. Remarkably, the majority of these procedures are performed in the complete absence of pre- or post-emptive analgesics. Recent clinical studies report that former NICU patients have increased thresholds for pain and stress later in life as compared with term-born infants. However, to date, the mechanisms whereby early-life inflammation alters later-life response to stress and pain are not known. The present studies were conducted to determine if neonatal injury impairs adult responses to anxiety- and stress-provoking stimuli. As we have previously reported that early-life pain results in a significant increase in opioid peptide expression within the midbrain periaqueductal gray, the role of endogenous opioids in our behavioral studies was also examined. Male and female rats received an intraplantar injection of the inflammatory agent carrageenan (1%) on the day of birth. In adulthood, animals were assessed for changes in response to anxiety- and stress-provoking stimuli using the open field and forced swim tests, respectively. Injury-induced changes in sucrose preference and stress-induced analgesia were also assessed. As adults, neonatally injured animals displayed a blunted response to both anxiety- and stress-provoking stimuli, as indicated by significantly more time spent in the inner area of the open field and a 2-fold increase in latency to immobility in the forced swim test as compared to controls. No change in sucrose preference was observed. Using in situ hybridization and immunohistochemistry, we observed a 2-fold increase in enkephalin mRNA and protein expression, respectively, in stress-related brain regions including the central amygdala and lateral septum. Administration of the opioid receptor antagonist naloxone reversed the attenuated responses to forced swim stress and stress-induced analgesia, suggesting the changes in stress-related behavior were opioid-dependent. Together, these data contribute to mounting evidence that neonatal injury in the absence of analgesics has adverse effects that are both long-term and polysystemic.

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Section: Discussionmentioning

confidence: 99%

A Single Neonatal Injury Induces Life-Long Deficits in Response to Stress

Victoria

Inoue²,

Young³

et al. 2013

Dev Neurosci

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“…Furthermore, early painful experiences may predispose infants and children to a later enhancement in both physiological and cognitive/emotional responses to noxious insult (Taddio et al, 1997;Alvares et al, 2000;Ruda et al, 2000;Lidow et al, 2001). Thus, it is imperative to understand age-specific regulation of pain pathways for the rational development of nonopioid analgesics for managing pain in infants and children.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C ϵ and γ: Involvement in Formalin-Induced Nociception in Neonatal Rats

Sweitzer

Wong²,

Peters³

et al. 2004

J Pharmacol Exp Ther

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The central nervous system undergoes dynamic changes as it matures. However, until recently, very little was known about the impact of these changes on pain and analgesia. This study tested the hypothesis that the ⑀ and ␥ isozymes of protein kinase C (PKC) contribute to formalin-induced nociception in an age-dependent manner. Expression of ⑀ and ␥ PKC and the contributions of these isozymes in formalin-induced nociception was examined in postnatal day 7, 15, and 21 rats. ⑀PKC expression in dorsal root ganglion neurons and ␥PKC expression in lamina II of the spinal cord increased from the first to the third postnatal week. Coupling immunohistochemical and Western analysis, translocation of ⑀PKC followed intraplantar formalin in all ages. In contrast, formalin-induced ␥PKC translocation was observed only in postnatal day 21 rats. Behaviorally, intrathecal administration of the ⑀PKC-specific inhibitor (⑀V1-2) attenuated phase 1 and phase 2 formalin behaviors at all ages. In contrast, intrathecal administration of the ␥PKC-specific inhibitor (␥V5-3) attenuated only phase 2 responses in postnatal day 15 and 21 rats. Functionally, inhibition of ⑀PKC decreased capsaicin-stimulated release of glutamate and calcitonin gene-related peptide in spinal cords isolated from postnatal day 7 rats. These results suggest that ⑀PKC age independently mediates inflammatory pain produced by intraplantar formalin. In contrast, ␥PKC contributes to formalin-induced nociception in an age-dependent manner. Identifying the molecular mechanisms responsible for age-specific patterns of nociception is necessary for the rational development of novel therapeutic strategies for treating pediatric pain.

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“…19,20,27,37,49 The effects of injury to neonatal animals on sensory processing in the adult has become a focus of attention. 3,4,29,42,48,53 Because experimental models differ in duration, intensity, and location of neonatal injury, differences in the direction of sensitivity alterations in adults are reported. For example, short duration neonatal hind paw injury can decrease or not change baseline somatic sensitivity in the adult and/or alter responses to subsequent injury in the adult.…”

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confidence: 99%