Abstract
Neonatal pain such as that experienced by infants in the neonatal intensive care unit is known to produce later-life dysfunction including heightened pain sensitivity and anxiety, although the mechanisms remain unclear. Both chronic pain and stress in adult organisms are known to influence the corticotropin-releasing factor (CRF) system in the Central Nucleus of the Amygdala, making this system a likely candidate for changes following neonatal trauma. To examine this, neonatal rats were subjected to daily pain, non-painful handling or left undisturbed for the first week of life. Beginning on postnatal day, 24 male and female rats were subjected to a 4-day fear conditioning and sensory testing protocol. Some subjects received intra-amygdalar administration of either Vehicle, the CRF receptor 1 (CRF1) receptor antagonist Antalarmin, or the CRF receptor 2 (CRF2) receptor antagonist Astressin 2B prior to fear conditioning and somatosensory testing, while others had tissue collected following fear conditioning and CRF expression in the CeA and BLA was assessed using fluorescent in situ hybridization. CRF1 antagonism attenuated fear-induced hypersensitivity in neonatal pain and handled rats, while CRF2 antagonism produced a general antinociception. In addition, neonatal pain and handling produced a lateralized sex-dependent decrease in CRF expression, with males showing a diminished number of CRF-expressing cells in the right CeA and females showing a similar reduction in the number of CRF-expressing cells in the left BLA compared to undisturbed controls. These data show that the amygdalar CRF system is a likely target for alleviating dysfunction produced by early life trauma and that this system continues to play a major role in the lasting effects of such trauma into the juvenile stage of development.
Highlights
Painful neonatal procedures are commonplace among infants admitted into neonatal intensive care units (NICUs), and many procedures are performed without the use of analgesics despite being rated as moderately to very painful (Porter et al, 1997; Roofthooft et al, 2014; Fitzgerald, 2015)
The effect of test session merely confirms that fear conditioning alters subsequent freezing to the conditioning context, whereas the interaction is of interest to our hypothesis that neonatal pain effects subsequent behavior
The current experiments demonstrate sex-dependent changes in amygdalar corticotropin-releasing factor (CRF) signaling in the lasting effects of neonatal trauma using a model that is representative of human NICU trauma
Summary
Painful neonatal procedures are commonplace among infants admitted into neonatal intensive care units (NICUs), and many procedures (e.g., heel lance, intravenous and/or arterial line insertions, endotracheal suctioning, etc.) are performed without the use of analgesics despite being rated as moderately to very painful (Porter et al, 1997; Roofthooft et al, 2014; Fitzgerald, 2015). The long-term negative effects of early life pain in humans are wellestablished. From human epidemiological data alone, it is not clear whether later-life dysfunction following NICU admission is the result of the painful procedures that occur in the NICU, concomitant factors such as lack of caregiver contact, or underlying health concerns and/or prematurity that led to placement in the NICU. Animal models can be used to experimentally manipulate non-human animals to better understand the impact of neonatal pain on later-life behavior and avoid or control these confounding factors. Neonatal pain has sometimes resulted in the decrease of subsequent fear and anxiety in rodents (Davis et al, 2018, 2020; Zuke et al, 2019; Xia et al, 2020), the literature is somewhat inconsistent (Anand et al, 1999)
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