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A single neonatal injury induces life-long deficits in response to stress
Nicole C Victoria1, Kiyoshi Inoue, Larry J Young
1Neuroscience Institute, Georgia State University, Atlanta, GA 30303, USA.
Insights
Neonatal pain from invasive procedures in the neonatal intensive care unit (NICU) can lead to long-term changes in stress and pain responses. These studies show early-life injury alters adult behavior via opioid pathways.
Area of Science:
- Neuroscience
- Developmental Biology
- Pain Research
Background:
- Premature infants in neonatal intensive care units (NICUs) undergo numerous painful procedures daily without adequate analgesia.
- Clinical studies suggest these infants develop altered pain and stress thresholds later in life.
- The underlying mechanisms linking early-life inflammatory pain to later-life behavioral changes remain largely unknown.
Purpose of the Study:
- To investigate if neonatal inflammatory injury impacts adult responses to anxiety- and stress-provoking stimuli.
- To explore the role of endogenous opioids in mediating these long-term behavioral alterations.
- To determine if neonatal pain affects stress-induced analgesia and sucrose preference in adulthood.
Main Methods:
- Neonatal rats received carrageenan injection to induce inflammation on the day of birth.
- Adult rats were assessed using the open field test (anxiety) and forced swim test (stress).
- Enkephalin expression was measured using in situ hybridization and immunohistochemistry; naloxone was used to block opioid receptors.
Main Results:
- Neonatally injured adult rats showed blunted responses to anxiety and stress, spending more time in the open field's center and exhibiting increased latency to immobility in the forced swim test.
- Enkephalin mRNA and protein levels were significantly increased in adult rat brain regions associated with stress and emotion.
- Opioid receptor antagonist naloxone administration reversed the attenuated behavioral responses, indicating an opioid-dependent mechanism.
Conclusions:
- Neonatal inflammatory injury, particularly without analgesia, induces long-lasting, multi-systemic adverse effects on stress and pain processing.
- Endogenous opioid pathways in the brain play a critical role in mediating these long-term behavioral changes.
- These findings highlight the importance of pain management in neonatal intensive care units to prevent chronic consequences.
Abstract:
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.
